Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
LY2216684 · 26 trials · 4 indications
Clinically significant events were defined as serious adverse events, regardless of causality. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Participants meeting any of the following criteria were determined as having major depressive disorder symptom re-emergence: 1) a Montgomery-Asberg Depression Rating Scale (MADRS) total score greater ≥14 or a Clinical Global Impressions of Severity (CGI-S) increase of 2 or more points from Week 18 at 2 consecutive visits or 2) discontinuation due to lack of efficacy/worsening of depression/suicidality. Time from randomization to the first visit at which the participant met the reemergence criteria was calculated. The percentage of participants who meet criteria was estimated using the Kaplan-Meier product limit method. The MADRS is a rating scale for severity of depressive mood symptoms and has a 10-item checklist with items rated on a scale of 0-6, for a total score range of 0 (low severity) to 60 (high severity). CGI-S measures severity of depression at the time of assessment compared with the start of treatment. Scores range from 1 (normal, not at all ill) to 7 (extremely ill).
The Montgomery-Asberg Depression Rating Scale (MADRS) is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist. Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS had a 10-item checklist (sadness \[apparent\], sadness \[reported\], inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Items were rated on a scale of 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
A clinically significant effect was defined as a serious adverse event, regardless of causality. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Assesses 18 Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision ADHD diagnosis symptoms/severity in past week. Each item: 0 (none/never, rarely) to 3 (severe/very often). Total score ranges from 0 to 54. Higher total scores indicate greater illness severity. Change scores=Week 8 score-baseline score. Least Squares (LS) Mean Change adjusted for fixed class effects of treatment, pooled investigative site, strata (prior stimulant use status), visit, and treatment\*visit interaction, and continuous, fixed effects of baseline score and baseline score\*visit interaction.
Assesses 18 Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision ADHD diagnosis symptoms/severity in past week. Each item: 0 (none/never, rarely) to 3 (severe/very often). Total score ranges from 0 to 54. Higher total scores indicate greater illness severity. Change scores=Week 8 score-baseline score. LS Mean Change adjusted for fixed class effects of treatment, pooled investigative site, strata (prior stimulant use status), visit, and treatment\*visit interaction, and continuous, fixed effects of baseline score and baseline score\*visit interaction.
The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS is a 10-item checklist with items rated on a scale of 0-6, for a total scores range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) means are calculated using mixed model repeating measures (MMRM) and adjusted for investigator, treatment-by-visit, baseline score, and baseline-by-visit.
The MADRS measured severity of depressive mood symptoms. The 10-item checklist rating scale was 0 to 6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Least Squares (LS) Means were adjusted for treatment, investigator, visit, treatment-by-visit, baseline score, and baseline-by-visit.
The HAMD-17 is a 17-item assessment used to assess the severity of depression and its improvement during the course of therapy. Each item was evaluated and scored using either a 5-point scale of 0 (not present/absent) to 4 (very severe) or a 3-point scale of 0 (not present/absent) to 2 (marked). Higher scores indicate greater symptom severity. The total score was the sum of the scores from HAMD-17 Items 1 through 17 and ranged from 0 (not at all depressed) to 52 (severely depressed). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, investigator, visit, baseline score, treatment-by-visit, and baseline score-by-visit.
AUC0-∞ of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric Least Squares (LS) mean and the 90% Confidence Interval (CI). Geometric LS mean was controlled by participant and treatment.
Cmax of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone, and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric LS mean and the 90% CI. Geometric LS mean was controlled by participant and treatment.
Tmax of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone, and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric LS mean and the 90% CI. Geometric LS mean was controlled by participant and treatment.
Blood samples were collected prior to and up to 120 hours following dosing of LY2216684 on Day 1 (Period 1) for the measurement of LY2216684 plasma concentrations.
Blood samples were collected prior to and up to 120 hours following dosing of LY2216684 on Day 1 (Period 1) for the measurement of LY2216684 plasma concentrations.
Blood samples were collected prior to and up to 120 hours following dosing of LY2216684 on Day 1 (Period 1) for the measurement of LY2216684 plasma concentrations.
The Cmax of LY2216684 was assessed. The Cmax was calculated for LY2216684 administered alone (reference) and LY2216684 co-administered with charcoal (test). Geometric LSMeans were calculated according to the following model: Log(PK) = sequence + period + treatment + subject + random error for Cmax.
Power of attention is a measure of focused attention and information processing speed; based on the summed reaction times from the simple reaction time, choice reaction time, and digit vigilance tasks. Scores are measured by response latencies, and smaller scores indicate better function. Least squares (LS) means were calculated using mixed model analysis of covariance (ANCOVA) adjusting for predose, sequence, period, day, time, treatment, and treatment\*time as fixed effects and participant within sequence and treatment as random effect.
Continuity of attention is a measure of sustained attention, combining (summed) accuracy and error measures from the choice reaction time and digit vigilance tasks. The number of correct responses (out of 50) for choice reaction time was added to the total number of targets correctly identified (out of 45) digit vigilance minus the number of false alarms (total score of -45 to 95). A high score reflects someone able to keep his/her mind on a single task for a prolonged period. A negative change from baseline reflects impairment compared to baseline. LS means were calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment\*time as fixed effects and participant within sequence and treatment as random effect.
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. LS means were calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment\*time as fixed effects and participant within sequence and treatment as random effect.
Assessed via the Bond and Lader Visual Analogue Scale (VAS), which utilizes a 16-point scale of 0 to 100 with 0 representing the worst rating and 100 representing the best rating. LS means were calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment\*time as fixed effects and participant within sequence and treatment as random effect.
The results presented are Geometric Least Squares (LS) mean. LS mean values were adjusted for treatment, sequence, period and participant.
The results presented are Geometric Least Squares (LS) mean. LS mean values were adjusted for treatment, sequence, period and participant.
Least Squares (LS) geometric mean was based on AUC0-∞ of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Least Squares (LS) geometric mean was based on Cmax of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
This outcome was measured based on Tmax of S-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test).
The geometric least squares mean and 90% Confidence Interval are presented. Geometric least squares mean corrected for participant, treatment and random error.
The geometric least squares mean and 90% Confidence Interval are presented. Geometric least squares mean corrected for participant, treatment and random error.
Cmax of digoxin when administered alone and when co-administered with LY2216684.
Tmax of digoxin when administered alone and when co-administered with LY2216684.
AUCt at steady state of digoxin when administered alone and when co-administered with LY2216684.
Heart rate was determined during ambulatory blood pressure monitoring (ABPM). Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Maximum and mean changes in ABPM heart rate were determined from a 24-hour continuous ABPM monitoring for Day 1 (0 to 24 hours). Least Squares (LS) mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect.
Heart rate was determined during ABPM. Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Maximum and mean changes in ABPM heart rate were determined from 24 hour continuous ABPM monitoring for Day 4 (0 to 24 hours). LS mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect.
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.
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.
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.
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.
R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684.
R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Log-transformed AUC0-tlast was analyzed using a linear mixed effects model with sequence, period, and treatment as fixed effects and participant as a random effect.
R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Log-transformed Cmax was analyzed using a linear mixed effects model with sequence, period, and treatment as fixed effects and participant as a random effect.
R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684.
The Least Squares (LS) geometric mean AUCτ of LY2216684 was calculated based on the LY2216684 plasma concentration time curve from time 0 hour (hr) to time 24 hr (tau \[τ\]) when LY221684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The Day 13-to-Day 3 ratio of the LY2216684 LS geometric mean of AUCτ and the associated 90% confidence interval (CI) of the ratio were calculated.
The Least Squares (LS) geometric mean Cmax of LY2216684 was determined when LY2216684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The Day 13-to-Day 3 ratio of the LY2216684 LS geometric mean of Cmax and the associated 90% confidence interval (CI) of the ratio were calculated.
Tmax of LY2216684 was determined using the median of paired differences between the 2 treatment groups when LY2216684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The 90% confidence interval (CI) for the median of differences was calculated.
The Least Squares (LS) geometric mean AUCτ of sertraline was calculated based on the sertraline plasma concentration time curve from time 0 hour (hr) to time 24 hr (tau \[τ\]) when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The Day 13-to-Day 10 ratio of the sertraline LS geometric mean of AUCτ and the associated 90% confidence interval (CI) of the ratio were calculated.
The Least Squares (LS) geometric mean Cmax of sertraline was determined when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The Day 13-to-Day 10 ratio of the sertraline LS geometric mean of Cmax and the associated 90% confidence interval (CI) of the ratio were calculated.
Tmax of sertraline was determined using the median of paired differences between the 2 treatment groups when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The 90% confidence interval (CI) for the median of differences was calculated.
The area under the plasma concentration versus time curve from 0 hours to infinity (AUC \[0-∞\]) for LY2216684 is presented.
| Arm | Type | Description |
|---|---|---|
| LY2216684 + SSRI | EXPERIMENTAL | LY2216684: 12 milligrams (mg) or 18 mg, administered orally, once daily for 52 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). During the open-label phase, all participants started at the 12 mg dose and could have the dose increased to 18 mg after the first week of treatment. During the first 12 weeks, participants were allowed (at scheduled or unscheduled visits) to decrease their dose to 12 mg based on response. After a decrease in dose to 12 mg, participants could have had an increase back up to 18 mg at any scheduled visit based on response and tolerability. After 12 weeks of treatment, participants maintained a stable dose. Open-label treatment was followed by a 1-week abrupt discontinuation phase. Participants who either completed study visits through Week 52 or discontinued early from the study for any reason returned 1 week later for follow-up visit. Participants did not receive LY2216684 but continued their SSRI treatment at a stable dose. |
| Placebo + SSRI | PLACEBO_COMPARATOR | Acute Open-label (OL) Period: Participants received a starting dose of 12 milligrams (mg) LY2216684, administered orally, once daily for at least 2 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI). Then, based on efficacy and tolerability, the dose could be increased to 18 mg (and decreased back to 12 mg) over the next 6 weeks. Stabilization OL Period: Participants meeting remission criteria continued on the same dose of LY2216684 for an additional 12 weeks. Participants who discontinued early during either OL Period were discontinued abruptly from LY2216684. Double-blind (DB) Randomized Withdrawal Period: At 20 weeks, participants meeting criteria for randomization were tapered from their LY2216684 dose to placebo following the regimen of 12 mg for 7 days, 6 mg for 7 days, and placebo for the remaining 22 weeks. Participants who completed this period or discontinued early continued to receive placebo for an additional 2 weeks |
| 12 or 18 mg flexible dose LY2216684 + SSRI | EXPERIMENTAL | LY2216684: flexible dose of 12 or 18 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Prior to entering the Adjunctive Treatment (AT) Phase, participants completed a 3-week Confirmation (CF) Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to a 12 or 18 mg flexible dose of LY2216684. During the AT Phase, participants first received 6 mg LY2216684 QD for 3 days, followed by 12 mg QD for the next 11 days. Then, based on efficacy and tolerability, dosage could be increased to 18 mg QD over the next 6 weeks. Participants on 18 mg QD could have had their dose decreased back to 12 mg QD. Participants who completed the AT Phase or discontinued early had the option to enter the Discontinuation (DC) Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment. |
| 6 mg fixed dose LY2216684 + SSRI | EXPERIMENTAL | LY2216684: fixed dose of 6 mg, administered orally, QD for 8 weeks, adjunctive to an SSRI Prior to entering the AT Phase, participants completed a 3-week CF Phase where they received placebo (orally, QD) adjunctive to their SSRI. After the CF Phase, and after randomization criteria were met, participants were randomized to 6 mg fixed dose of LY2216684. During the AT Phase, participants received a 6 mg fixed dose of LY2216684 adjunctive to their SSRI for 8 weeks. Participants who completed the AT Phase or discontinued early had the option to enter the DC Phase. During the 1-week abrupt DC Phase, participants maintained their SSRI treatment. |
| 12 milligrams (mg) LY2216684 + SSRI | EXPERIMENTAL | LY2216684: 12 milligrams (mg), administered orally, once daily (QD) for 8 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Prior to entering the Adjunctive Treatment (AT) Phase, participants completed a 3-week Confirmation (CF) Phase where they received placebo (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the LY2216684 12-mg treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early entered a 2-week Discontinuation (DC) Phase. Participants were randomly assigned to either abrupt DC or tapered DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase. |
| 18 milligrams (mg) LY2216684 + SSRI | EXPERIMENTAL | LY2216684: 12 milligrams (mg), administered orally, once daily (QD) for 1 week, followed by 18 mg, administered orally, once daily for 7 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) Prior to entering the Adjunctive Treatment (AT) Phase, participants completed a 3-week Confirmation (CF) Phase where they received placebo (administered orally, QD) adjunctive to their SSRI. After the CF Phase and after randomization criteria were met, participants were randomized to the LY2216684 18-mg treatment arm (AT Phase). Participants who completed the AT Phase or discontinued early entered a 2-week Discontinuation (DC) Phase. Participants were randomly assigned to either abrupt DC or tapered DC over the 2-week DC Phase. Participants maintained their SSRI treatment during the DC Phase. |
| LY2216684 (edivoxetine) + SSRI | EXPERIMENTAL | - |
| Methylphenidate | ACTIVE_COMPARATOR | Extended-release methylphenidate 18 milligrams per day (mg/day) to 54 mg/day, based on weight, given once daily (QD) and orally (po) as a capsule for the 8-week double-blind treatment phase, followed by 2 weeks of placebo in the taper phase. |
| Placebo | PLACEBO_COMPARATOR | - |
| LY2216684 (0.1 mg/kg/day) | EXPERIMENTAL | Taken in tablet form QD po for the 8-week double-blind treatment phase, followed by 2 weeks of placebo in the taper phase. |
| LY2216684 (0.2 mg/kg/day) | EXPERIMENTAL | Taken in tablet form QD po for the 8-week double-blind treatment phase, followed by 2 weeks of tapering in the taper phase. |
| LY2216684 (0.3 mg/kg/day) | EXPERIMENTAL | Taken in tablet form QD po for the 8-week double-blind treatment phase, followed by 2 weeks of tapering in the taper phase. |
| LY2216684 | EXPERIMENTAL | - |
| Escitalopram | ACTIVE_COMPARATOR | Escitalopram: flexible dose of 10 or 20 milligram (mg), capsules, administered orally, once daily for 8 weeks. For the first week of treatment, participants received a starting dose of 10 mg/day. Then, based on tolerability, for the next 7 weeks, the dose could remain at 10 mg/day; it could be increased up to a maximum dose of 20 mg/day; or it could be decreased back to 10 mg/day. All participants were required to take an equal number of tablets (2) and capsules (2) per day. Therefore, participants on 10 mg/day of escitalopram also received 1 escitalopram-matching placebo capsule + 2 LY2216684-matching placebo tablets. Participants on 20 mg/day of escitalopram also received 2 LY2216684-matching placebo tablets. |
| LY2216684 + Clarithromycin | EXPERIMENTAL | Participants will receive a single 18-mg oral dose of LY2216684 on Days 1 and 10. Clarithromycin (500 mg) will be administered twice a day (BID) on Days 6 through 13. |
| LY2216684 + Quinidine (CYP2C19 poor metabolizers) | EXPERIMENTAL | Participants were predicted to have a cytochrome P450 (CYP)2C19 poor metabolizer (PM) phenotype, as determined by genotyping analysis. Period 1 (Days 1-7): a single, oral dose of 18 milligrams (mg) LY2216684 was administered on Day 1. Period 2 (Days 8-15): 300 mg quinidine sulfate controlled release was administered orally, once daily on Days 8-15. Additionally, a single, oral dose of 18 mg LY2216684 was administered on Day 11. |
| LY2216684 (CYP2C19 extensive metabolizers) | EXPERIMENTAL | Participants were predicted to have a cytochrome P450 (CYP)2C19 extensive metabolizer (EM) phenotype, as determined by genotyping analysis. Period 1 (Days 1-7): a single, oral dose of 18 milligrams (mg) LY2216684 administered on Day 1. Period 2 (Days 8-15): EM participants did not participate in this period. |
| LY2216684 administered in fasted then fed state | EXPERIMENTAL | Period 1: Single 18-mg (milligram) oral dose of LY2216684 administered in fasted state. Period 2: Single 18-mg oral dose of LY2216684 administered in fed state. Periods will be separated by a minimum of 7 days. |
| LY2216684 administered in fed then fasted state | EXPERIMENTAL | Period 1: Single 18-mg oral dose of LY2216684 administered in fed state. Period 2: Single 18-mg oral dose of LY2216684 administered in fasted state. Periods will be separated by a minimum of 7 days. |
| LY2216684 without Charcoal, then with Charcoal | EXPERIMENTAL | Period 1: Single 18-mg (milligram) (two 9-mg tablets) oral dose of LY2216684 administered without Activated Charcoal. Period 2: Single 18-mg (two 9-mg tablets) oral dose of LY2216684 administered with single oral dose of 1 g/kg (gram/kilogram) of Activated Charcoal. Periods will be separated by a minimum of 7 days. |
| LY2216684 with Charcoal, then without Charcoal | EXPERIMENTAL | Period 1: Single 18-mg (two 9-mg tablets) oral dose of LY2216684 administered with single oral dose of 1 g/kg of Activated Charcoal. Period 2: Single 18-mg (two 9-mg tablets) oral dose of LY2216684 administered without Activated Charcoal. Periods will be separated by a minimum of 7 days. |
| LY, Alc, Pl-Match Alc, Then Pl-Match LY, Alc, Pl-Match Alc | EXPERIMENTAL | Period 1: 18 milligrams (mg) LY2216684 (LY) administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of an alcoholic (Alc) beverage (with an alcohol dose of 0.6 grams per kilograms \[g/kg\] for women and 0.7 g/kg for men), taken orally, one time. On Day 8, participants were administered 2 cups of a placebo-matching (Pl-Match) alcoholic beverage, taken orally, one time. Period 2: Placebo-matching LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. On Day 8, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. There was a 7-day washout period between Periods 1 and 2. |
| Pl-Match LY, Alc, Pl-Match Alc, Then LY, Alc, Pl-Match Alc | EXPERIMENTAL | Period 1: Placebo-matching LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. On Day 8, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. Period 2: 18 mg LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. On Day 8, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. There was a 7-day washout period between Periods 1 and 2. |
| LY, Pl-Match Alc, Alc, Then Pl-Match LY, Pl-Match Alc, Alc | EXPERIMENTAL | Period 1: 18 mg LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. On Day 8, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. Period 2: Placebo-matching LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. On Day 8, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. There was a 7-day washout period between Periods 1 and 2. |
| Pl-Match LY, Pl-Match Alc, Alc, Then LY, Pl-Match Alc, Alc | EXPERIMENTAL | Period 1: Placebo-matching LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. On Day 8, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. Period 2: 18 mg LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. On Day 8, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. There was a 7-day washout period between Periods 1 and 2. |
| OC + LY2216684 First, Then OC + Placebo | EXPERIMENTAL | 28-day lead-in period of Ortho Cyclen (OC; 28-day packet), followed by randomization to OC administered orally once daily for 28 days + 18 milligrams (mg) of LY2216684 administered concomitantly orally once daily for 21 days, followed by OC administered orally once daily for 28 days + placebo administered concomitantly orally once daily for 21 days. |
| OC + Placebo First, Then OC + LY2216684 | EXPERIMENTAL | 28-day lead-in period of OC (28-day packet), followed by randomization to OC administered orally once daily for 28 days + placebo administered concomitantly orally once daily for 21 days, followed by OC administered orally once daily for 28 days + 18 mg of LY2216684 administered concomitantly orally once daily for 21 days. |
| Warfarin, LY2216684 + Warfarin | EXPERIMENTAL | Period 1: Single 10-milligram (mg) warfarin oral dose on Day 1; Washout Period of at least 14 days; Period 2: 18-mg LY2216684 oral dose, once daily on Days 1 to 12, with single 10-mg warfarin oral dose coadministered on Day 3. |
| LY2216684+lorazepam, placebo+lorazepam | EXPERIMENTAL | Oral 18 mg doses of LY2216684 on days 1-6 with a single oral 1 mg dose of lorazepam on day 3 in treatment period 1. Oral doses of placebo on days 1-6 with a single oral 1 mg dose of lorazepam on day 3 in treatment period 2. There is a washout period of at least 7 days between dosing periods. |
| Placebo+Lorazepam, LY2216684+Lorazepam | EXPERIMENTAL | Oral doses of placebo on days 1-6 with a single oral 1 mg dose of lorazepam on day 3 in treatment period 1. Oral 18 mg doses of LY2216684 on days 1-6 with a single oral 1 mg dose of lorazepam on day 3 in treatment period 2. There is a washout period of at least 7 days between dosing periods. |
| LY2216684 + digoxin | EXPERIMENTAL | Two oral 0.5-milligrams (mg) (two 0.25-mg tablets) doses of digoxin separated by 12 hours on Day 1, followed by once daily 0.25-mg (single 0.25-mg tablet) dose of digoxin on Days 2-14. Daily oral 18-mg (two 9-mg tablets) doses of LY2216684 on Days 8-14. |
| LY2216684, placebo, LY or placebo | EXPERIMENTAL | Period 1: 18 milligrams (mg) LY2216684 administered orally once daily on Days 1-4 Period 2: placebo administered orally once daily on Days 1-4 Period 3: 36 mg LY2216684 or placebo administered orally daily on Days 1-4 |
| Placebo, LY2216684, placebo or LY | EXPERIMENTAL | Period 1: placebo administered orally once daily on Days 1-4 Period 2: 18 mg LY2216684 administered orally once daily on Days 1-4 Period 3: 36 mg LY2216684 or placebo administered orally daily on Days 1-4 |
| LY2216684, albuterol, LY2216684+albuterol | EXPERIMENTAL | 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. |
| albuterol, LY2216684+albuterol, LY2216684 | EXPERIMENTAL | 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. |
| LY2216684+albuterol, LY2216684, albuterol | EXPERIMENTAL | 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. |
| LY2216684, propranolol, LY2216684+propranolol | EXPERIMENTAL | 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. |
| propranolol, LY2216684+propranolol, LY2216684 | EXPERIMENTAL | 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. |
| LY2216684+propranolol, LY2216684, propranolol | EXPERIMENTAL | 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. |
| Theophylline, LY2216684 + Theophylline | EXPERIMENTAL | 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 |
| LY2216684 + Theophylline, Theophylline | EXPERIMENTAL | 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 |
| Clopidogrel First, Then LY2216684 + Clopidogrel | EXPERIMENTAL | Period 1: a single 300-milligram (mg) dose of clopidogrel administered orally on Day 1 (Treatment 1). Period 2: an 18-mg dose of LY2216684 administered orally, once daily (QD) on Days 1 through 3, plus a single 300-mg dose of clopidogrel administered orally on Day 3 (Treatment 2). There was a washout period of at least 14 days between the last dose of study drug in Period 1 and the first dose in Period 2. |
| LY2216684 + Clopidogrel First, Then Clopidogrel | EXPERIMENTAL | Period 1: an 18-milligram (mg) dose of LY2216684 administered orally, once daily (QD) on Days 1 through 3, plus a single 300-mg dose of clopidogrel administered orally on Day 3 (Treatment 2). Period 2: a single 300-mg dose of clopidogrel administered orally on Day 1 (Treatment 1). There was a washout period of at least 14 days between the last dose of study drug in Period 1 and the first dose in Period 2. |
| LY2216684/sertraline/LY2216684 + sertraline | EXPERIMENTAL | Period 1: LY2216684 18 milligram (mg) oral (po) dose on Days 1-3. Period 2: Sertraline 50 mg po dose on Day 4 followed by sertraline 100 mg po dose on Days 5-10. Period 3: LY2216684 18 mg po dose + sertraline 100 mg po dose on Days 11-13. |
| LY2216684 + fluoxetine | EXPERIMENTAL | LY2216684: 18 milligrams (mg) oral (po) once daily (QD) on Days 1, 2, and 3 and Days 25-27 Fluoxetine: 60 mg po QD for 7 days (Days 4-10) then 20 mg po QD for 17 days (Days 11-27) |
| Name | Type | Description |
|---|---|---|
| LY2216684 | DRUG | - |
| SSRI | DRUG | Participants were to enter the study taking their current stable SSRI treatment dose and maintain the same dose throughout the study. |
| Placebo | DRUG | - |
| LY2216684 (edivoxetine) | DRUG | 12 to 18 milligrams (mg), administered orally, once daily for 54 weeks, adjunctive to a selective serotonin reuptake inhibitor (SSRI) |
| Methylphenidate | DRUG | Extended-release methylphenidate 18 mg/day to 54 mg/day, based on weight, QD po as a capsule for the 8-week double-blind treatment phase. |
| Placebo (tablet) | DRUG | Placebo given as a tablet for LY2216684 blind QD po for the 8-week double-blind treatment phase, followed by 2 weeks in the taper phase. |
| Placebo (capsule) | DRUG | Placebo given as a capsule for methylphenidate blind QD po for the 8-week double-blind treatment phase followed by 2 weeks in the taper phase. |
| Escitalopram | DRUG | 10-mg capsules |
| Clarithromycin | DRUG | Administered orally |
| Quinidine | DRUG | - |
| Activated Charcoal | DRUG | Administered orally |
| Placebo-matching LY2216684 | DRUG | Administered orally |
| Placebo-matching alcoholic beverage | DRUG | Administered orally |
| Alcoholic beverage | DRUG | Administered orally |
| Ortho Cyclen | DRUG | 35 micrograms (mcg) ethinyl estradiol and 250 mcg norgestimate administered orally |
| Warfarin | DRUG | 10-mg warfarin oral dose |
| Lorazepam | DRUG | Administered orally |
| Digoxin | DRUG | Administered orally |
| albuterol | DRUG | administered orally |
| propranolol | DRUG | administered orally |
| placebo for LY2216684 | DRUG | administered orally |
| placebo for albuterol | DRUG | administered orally |
| placebo for propranolol | DRUG | administered orally |
| Theophylline | DRUG | 200-mg theophylline oral dose |
| Clopidogrel | DRUG | - |
| Sertraline | DRUG | po administration |
| Fluoxetine | DRUG | Fluoxetine: 60 mg po QD for 7 days (Days 4-10) then 20 mg po QD for 17 days (Days 11-27) |
Inclusion Criteria: * Participants must have completed Study LNBM: NCT01173601 or Study LNBQ: NCT01187407 * Participants must be competent and able to give their own informed consent Exclusion Criteria: * Participants that have had or currently have any additional ongoing Diagnostic and Statistic...
LY2216684 is an investigational small molecule being studied for psychiatric conditions, including Major Depressive Disorder (MDD), Depressive Disorder Major, and Attention Deficit Hyperactivity Disorder. It has been evaluated as an adjunctive treatment for patients with MDD who had a partial response to selective serotonin reuptake inhibitor (SSRI) treatment.
LY2216684 is being developed by Eli Lilly and Company, a pharmaceutical company traded on the NYSE under the ticker symbol LLY. The drug is an investigational small molecule in the psychiatry therapeutic area.
LY2216684 is in Phase 2 of clinical development. It has completed 15 clinical trials, including Phase 1 and Phase 3 studies, with a total enrollment of 4,762 participants. The drug is not approved and remains under investigation.
LY2216684 has completed several clinical trials, including NCT01187407, a Phase 3 study of flexible or fixed dose LY2216684 as adjunctive treatment for Major Depressive Disorder with partial response to SSRI treatment, enrolling 1,480 participants across multiple countries.
LY2216684 is also known as edivoxetine. It is an investigational drug being developed by Eli Lilly and Company for psychiatric conditions such as Major Depressive Disorder and Attention Deficit Hyperactivity Disorder.