A Study of LY2216684 in Participants With Major Depression Disorder

Long-Term, Open-Label, Safety Study of LY2216684 12 to 18 mg Once Daily as Adjunctive Treatment for Adult Patients With Major Depressive Disorder Who Were Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01370499

Enrollment

288

Registered

2011-06-10

Start date

2011-08-31

Completion date

2014-01-31

Last updated

2018-10-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Major Depressive Disorder

Brief summary

The primary objective of this study is to evaluate the long-term safety and tolerability of LY2216684 administered once daily in the adjunctive treatment with an Selective Serotonin Reuptake Inhibitors (SSRI) for up to approximately 1 year in participants with Major Depressive Disorder (MDD) who were partial responders to their SSRI treatment.

Interventions

DRUGLY2216684

DRUGSSRI

Participants were to enter the study taking their current stable SSRI treatment dose and maintain the same dose throughout the study.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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 Statistical Manual of Mental Disorder, fourth edition, text revision (DSM-IV-TR) Axis I condition other than major depression that was considered the primary diagnosis within 1 year of entering trial * Participants that have had any anxiety disorder that was considered a primary diagnosis within the past year * Participants that have a current or previous diagnosis of bipolar disorder, schizophrenia, or other psychotic disorder * Participants that have a history of substance abuse within the past 1 year, and/or substance dependence within the past 1 year, not including caffeine and nicotine * Participants that have an Axis II disorder that, in the judgment of the investigator, would interfere with compliance with the study * Participants that have had a lack of full response of the current depressive episode to 2 or more adequate courses of antidepressant therapy at a clinically appropriate dose for at least 4 weeks, or in the judgment of the investigator, the participant has treatment-resistant depression * Participants that have a history of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or psychosurgery within the last year * Participants who are women who are pregnant or breastfeeding * Participants who, in the opinion of the investigator, are judged to be at serious risk for harm to self or others * Participants that have a serious or unstable medical illness * Participants that have any diagnosed medical condition which could be exacerbated by noradrenergic agents * Participants that have a history of severe allergies to more than 1 class of medication or multiple adverse drug reactions * Participants that have a history of any seizure disorder (other than febrile seizures) * Participants that have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to entering trial or have a potential need to use an MAOI within 3 days after discontinuation from the study * Participants that require psychotropic medication other than sedative/hypnotic medication for sleep * Participants who are taking or have received treatment with any excluded medications within 7 days prior to entering trial * Participants that have a thyroid stimulating hormone (TSH) level outside the laboratory established reference range. Participants previously diagnosed with hyperthyroidism or hypothyroidism who have been treated with a stable dose of thyroid supplement for at least the past 3 months, and who are clinically and chemically euthyroid will be allowed to participate in the study. * Participants that have initiated or discontinued hormone therapy within the previous 3 months prior to enrollment * Participants that have initiated psychotherapy, change in intensity of psychotherapy or other nondrug therapies (such as acupuncture or hypnosis) within 6 weeks prior to enrollment or at any time during the study. * Participants have a positive urine drug screen (UDS) for any substances of abuse on entering trial * Participants have significantly violated rules that a participant must comply with during Study LNBM: NCT01173601 or Study LNBQ: NCT01187407

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Clinically Significant Events	Baseline through 52 weeks	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.

Secondary

Measure	Time frame	Description
Change From Baseline to 52 Week Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score and Individual Items	Baseline, 52 weeks	The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has 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 are 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 pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in Clinical Global Impression - Severity (CGI-S)	Baseline, 52 weeks	Clinical Global Impression - 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 (among the most extremely ill participants). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in Fatigue Associated With Depression (FAsD) Average Score and Subscale Scores	Baseline, 52 weeks	The FAsD is a participant-rated scale with a total of 13 items. Six of the 13 items ask how often participants experience different aspects of fatigue with responses from 1 (never) to 5 (always). Seven of the 13 items ask how often fatigue impacts various aspects of the participant's lives with responses from 1 (not at all) to 5 (very much). The Experience Score was derived by taking the mean of Items 1 through 6, the Impact Score was derived by taking the mean of Items 7 through 13 (applicable items only), and the Average Score was the mean of Items 1 through 13 (derived by taking the mean of all applicable items for each participant). Item 12 applied only to participants with a spouse or significant other and Item 13 applied to participants who had a job or who went to school. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety Subscale Scores	Baseline, 52 weeks	The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire with 2 subscales: anxiety and depression. The anxiety subscale score is the sum of the 7 odd-numbered items and depression subscale score is the sum of the 7 even-numbered items, giving maximum scores of 21 for each subscale. Scores of 11 or more on either subscale were considered to be a 'significant' case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7, 'normal'. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in Sheehan Disability Scale (SDS) Total Score and Subscale Scores	Baseline, 52 weeks	The SDS Global Functional Impairment Score (total score) and subscores were completed by the participant and were used to assess the effect of the participant's symptoms on his or her work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. The Global Functional Impairment Score is the sum of the 3 items, and scores ranged from 0 to 30 with high values indicating greater disruption in the participant's work life (work/school impairment score), social life (social life/leisure activities impairment score), and family life (family life/home responsibilities impairment score). Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Percentage of Participants With Suicidal Behaviors and Ideations Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS)	Baseline through 52 weeks	The C-SSRS captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation was defined as a yes answer to any 1 of 5 suicidal ideation questions, which included a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior was defined as a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as treatment-emergent (TE) if not present at baseline. Percentage of participants was calculated by dividing the number of participants with suicide-related events by the total number of participants at risk, multiplied by 100%. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Change From Baseline to 52 Week Endpoint in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)	Baseline, 52 weeks	The Q-LES-Q-SF is a self-administered 16-item questionnaire measuring degree of enjoyment and satisfaction experienced in various areas of daily life during the past week on a 5-point Likert scale (1=very poor and 5=very good). The total possible scores range from 16 to 80. Higher scores indicate higher levels of enjoyment/satisfaction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ)	Baseline, 52 weeks	The CPFQ is a 7-item participant-rated questionnaire pertaining to a participant's cognitive and physical well-being. It assesses motivation, wakefulness, energy, focus, recall, word-finding difficulty, and mental acuity. Each item is scored on a 6-point scale ranging from 1 (greater than normal) to 6 (totally absent). Total scores ranged from 7 to 42. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in Arizona Sexual Experiences (ASEX) Scale	Baseline, 52 weeks	The Arizona Sexual Experiences (ASEX) scale is used to assess sexual functioning in both males and females. The ASEX total score for the male and female version is calculated as the sum of the responses (rated from 1 \[extremely\] to 6 \[no/never\]) to the 5 items of the ASEX scale. Total scores ranged from 5 to 30, with higher scores indicating greater sexual dysfunction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in Blood Pressure	Baseline, 52 weeks	Blood pressure measurements were collected when the participant was in a sitting position. Three measurements of sitting blood pressure collected at approximately 1-minute intervals at every visit were averaged and used as the value for the visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in Pulse Rate	Baseline, 52 weeks	Pulse measurements were collected when the participant was in a sitting position. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.
Change From Baseline to 52 Week Endpoint in EuroQol Questionnaire - 5 Dimension (EQ-5D)	Baseline, 52 weeks	The 5Q-5D Visual Analog Scale is a generic, multidimensional, health-related, quality-of-life instrument. Overall health state score is self-reported using a visual analogue scale, marked on a scale of 0 to 100 with 0 representing worst imaginable health state and 100 representing best imaginable health state. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.

Countries

Japan

Participant flow

Pre-assignment details

This is an open-label study with 1 treatment (12 or 18 milligrams \[mg\] LY2216684 + SSRI). However, the data were analyzed by the participants' treatment group from 2 parent studies (Study LNBM: NCT01173601 or Study LNBQ: NCT01187407). In these prior, parent studies, participants were randomized to receive Placebo + SSRI or LY2216684 + SSRI.

Participants by arm

Arm	Count
LY2216684 + SSRI (Placebo Prior Study) LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	195
LY2216684 + SSRI (LY2216684 Prior Study) LY2216684: 12 mg or 18 mg, administered orally, once daily for 52 weeks, adjunctive to an SSRI	93
Total	288

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	38	12
Overall Study	Lack of Efficacy	4	2
Overall Study	Lost to Follow-up	2	1
Overall Study	Physician Decision	3	3
Overall Study	Protocol Violation	5	4
Overall Study	Sponsor Decision	41	15
Overall Study	Withdrawal by Subject	18	7

Baseline characteristics

Characteristic	LY2216684 + SSRI (LY2216684 Prior Study)	Total	LY2216684 + SSRI (Placebo Prior Study)
Age, Continuous	37.40 years STANDARD_DEVIATION 9.18	38.68 years STANDARD_DEVIATION 9.36	39.28 years STANDARD_DEVIATION 9.41
Race/Ethnicity, Customized Asian	93 Participants	288 Participants	195 Participants
Region of Enrollment Japan	93 Participants	288 Participants	195 Participants
Sex: Female, Male Female	45 Participants	133 Participants	88 Participants
Sex: Female, Male Male	48 Participants	155 Participants	107 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	158 / 195	67 / 92	9 / 188	3 / 84
serious Total, serious adverse events	1 / 195	2 / 92	0 / 188	0 / 84

Outcome results

Primary

Number of Participants With Clinically Significant Events

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.

Time frame: Baseline through 52 weeks

Population: All participants who took at least one dose of study medication and did not discontinue from the study for the reason 'Lost to follow-up' at the first post-baseline visit.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
LY2216684 + SSRI (Placebo Prior Study)	Number of Participants With Clinically Significant Events	Contusion	0 Participants
LY2216684 + SSRI (Placebo Prior Study)	Number of Participants With Clinically Significant Events	Hyperglycaemia	0 Participants
LY2216684 + SSRI (Placebo Prior Study)	Number of Participants With Clinically Significant Events	Subdural hygroma	1 Participants
LY2216684 + SSRI (LY2216684 Prior Study)	Number of Participants With Clinically Significant Events	Contusion	1 Participants
LY2216684 + SSRI (LY2216684 Prior Study)	Number of Participants With Clinically Significant Events	Hyperglycaemia	1 Participants
LY2216684 + SSRI (LY2216684 Prior Study)	Number of Participants With Clinically Significant Events	Subdural hygroma	0 Participants

Secondary

Change From Baseline to 52 Week Endpoint in Arizona Sexual Experiences (ASEX) Scale

The Arizona Sexual Experiences (ASEX) scale is used to assess sexual functioning in both males and females. The ASEX total score for the male and female version is calculated as the sum of the responses (rated from 1 \[extremely\] to 6 \[no/never\]) to the 5 items of the ASEX scale. Total scores ranged from 5 to 30, with higher scores indicating greater sexual dysfunction. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for pooled investigative site and visit, baseline score, and baseline score-by-visit interaction.