Safety and Tolerability of Vortioxetine (LuAA21004) - Open Label Extension Study

A Phase 3, Long-Term, Open-Label, Flexible-Dose, Extension Study Evaluating the Safety and Tolerability of Lu AA21004 (15 and 20 mg) in Subjects With Major Depressive Disorder

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01152996

Enrollment

1075

Registered

2010-06-29

Start date

2010-09-30

Completion date

2013-05-31

Last updated

2014-05-28

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

Conditions

Depressive Disorder, Major

Keywords

Depression, Melancholia, Paraphrenia, Drug Therapy

Brief summary

The purpose of this study is to determine the long-term safety and tolerability of vortioxetine, once daily (QD), in participants with major depressive disorder.

Detailed description

Depression has been recognized as a chronic illness that imposes a significant burden on individuals, families and society. Major depressive disorder (MDD) is among the most important causes of disability worldwide, in both developing and developed countries. Major depressive disorder is reported to be the most common mood disorder, with a lifetime prevalence of about 15% and as high as 25% in women. Major depressive disorder is characterized by the presence of 1 or more major depressive episodes that presents with depressed mood, loss of interest or pleasure, disturbed sleep or appetite, low energy, feelings of guilt or low self-worth, and poor concentration. This is a multicenter extension study designed to allow eligible patients who have completed short-term efficacy and safety studies LuAA21004\_315 (NCT01153009), LuAA21004\_316 (NCT01163266) and LuAA21004\_317 (NCT01179516) to receive the 52-week treatment with vortioxetine in this open-label extension study. Participants are expected to return to the site for approximately 13 visits. A safety follow-up call will be made 4 weeks after completion of the 52-week treatment period.

Interventions

DRUGVortioxetine

Vortioxetine tablets

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 77 Years

Healthy volunteers

Inclusion criteria

* Has completed either study LuAA21004\_315 ( NCT01153009), LuAA21004\_316 (NCT01163266), or LuAA21004\_317 (NCT01179516) immediately prior to enrollment in the extension study (ie, the baseline visit is the same visit as the Week 8 \[Lu AA21004\_317\] or Week 10 \[Lu AA21004\_315 or Lu AA21004\_316\] assessment of the preceding protocol). * Suffers from a recurrent major depressive episode) as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria (classification code 296.3x) at entry into the prior study. * Twelve-month continuation treatment with Lu AA21004 is indicated for the treatment of this participant according to the opinion of the investigator. * Females of childbearing potential who are sexually active with a nonsterilized male partner agree to routinely use adequate contraception throughout the duration of the study.

Exclusion criteria

* Has Major Depressive Disorder for whom other psychiatric disorders (mania, bipolar disorder, schizophrenia, or any psychotic disorder) have been diagnosed during the prior study. * In the investigator's clinical judgment, has a significant risk of suicide and/or a score of ≥5 points on item 10 (suicidal thoughts) of the Montgomery Åsberg Depression Rating Scale (MADRS). * In the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any reason. * Has a clinically significant moderate or severe ongoing adverse event related to study medication from the prior study. * Has used/uses disallowed concomitant medication.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Over the 52 week period	Treatment-emergent adverse events (TEAE) are adverse events with an onset that occurs after receiving study drug and within 30 days after receiving the last dose of study drug. A TEAE may also be a pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug that increases in severity after the start of dosing.
Number of Participants With Serious Treatment-Emergent Adverse Events	Over the 52 week period	Serious treatment-emergent adverse events (serious-TEAE) are adverse events with an onset that occurs after receiving study drug and within 30 days after receiving the last dose of study drug. A serious-TEAE may also be a pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug that increases in severity after the start of dosing. Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered serious adverse events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.
Treatment-Emergent Adverse Events Leading to Study Discontinuation	Over the 52 week period	Treatment-emergent adverse events are adverse events with an onset that occurs after receiving study drug and within 30 days after receiving the last dose of study drug. A TEAE may also be a pre-treatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug that increases in severity after the start of dosing.

Secondary

Measure	Time frame	Description
Change From Baseline in Sheehan Disability Scale (SDS) Total Score	Baseline and Weeks 12, 24, 36, and 52	The change between the SDS total score at each assessed visit and the total score collected at baseline. The SDS is a 3 item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over three inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11 point scale from 0 (not at all) to 10 (extremely) with a total score range from 0 to 30. Higher scores indicate greater severity of impairment.
Change From Baseline in SDS Work/School Subscale	Baseline and Weeks 12, 24, 36, and 52	The change between the Sheehan Disability work/school subscale score at each assessed visit and work/school subscale score collected at baseline. The SDS is a 3 item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over three inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11 point scale from 0 (not at all) to 10 (extremely). Higher scores indicate greater severity of impairment.
Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score	Baseline and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52	The change between MADRS total score at each assessed visit and MADRS score at baseline. MADRS is a 10-item clinician rated scale to measure overall severity of depressive symptoms (i.e., apparent sadness, reported sadness, inner tension, etc.) rated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal) with a total score range from 0 to 60. Higher scores indicate greater severity of symptoms.
Change From Baseline in SDS Family Life/Home Responsibilities Subscale	Baseline and Weeks 12, 24, 36, and 52	The change between the Sheehan Disability family life/home responsibilities subscale score at each assessed visit and family life/home responsibilities subscale score collected at baseline. The SDS is a 3 item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over three inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11 point scale from 0 (not at all) to 10 (extremely). Higher scores indicate greater severity of impairment.
Change From Baseline in SDS Social Life Subscale	Baseline and Weeks 12, 24, 36, and 52	The change between the Sheehan Disability social life subscale score at each assessed visit and social life subscale score collected at baseline. The SDS is a 3 item rating scale to assess functional impairment (panic, anxiety, phobic and depressive symptoms) over three inter-related domains (work/school, social life, and family life/home responsibilities) rated on an 11 point scale from 0 (not at all) to 10 (extremely). Higher scores indicate greater severity of impairment.
Change From Baseline in the Hamilton Anxiety Scale (HAM-A) Total Score	Baseline and Weeks 4, 24, and 52	The change between HAM-A score at each assessed visit and HAM-A score at baseline. HAM-A is a 14 item rating scale to quantify anxiety symptomatology severity (i.e., anxious mood, tension, fear, insomnia, etc.) rated on a 5-point scale from 0 (not present) to 4 (severe) with a total score range from 0 to 56. Higher scores indicate greater severity of symptoms.
Change From Baseline in Clinical Global Impression Scale-Severity of Illness (CGI-S)	Baseline and Weeks 4, 24, and 52	The change between CGI-S score at each assessed visit and CGI-S score at baseline. The CGI-S assesses the clinician's impression of the subject's current state of mental illness and consists of one question for the investigator: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? which is rated on a seven-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=extremely ill). Higher scores indicate greater severity of illness.

Participant flow

Recruitment details

Participants took part in the study at 143 investigative sites in the United States from 07 Sep 2010 to 31 May 2013.

Pre-assignment details

Patients who completed Studies LuAA21004\_315 (NCT01153009), LuAA21004\_316 (NCT01163266), and LuAA21004\_317 (NCT01179516) and were willing to continue, and judged by the investigator to benefit from a 52-week continuation treatment with Lu AA21004, were enrolled and received flexible doses of study drug, based on patient response and tolerability.

Participants by arm

Arm	Count
Vortioxetine Vortioxetine 10 mg, capsules, orally, once daily for the first week of treatment; then vortioxetine up-titrated to 15 mg or 20 mg, capsules, orally, once daily for up to 51 weeks.	1,075
Total	1,075

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	115
Overall Study	Elevated liver enzymes	1
Overall Study	Lack of Efficacy	68
Overall Study	Lost to Follow-up	112
Overall Study	Noncompliance	41
Overall Study	Other	36
Overall Study	Protocol Violation	22
Overall Study	Withdrawal by Subject	142

Baseline characteristics

Characteristic	Vortioxetine
Age, Continuous	44.5 years STANDARD_DEVIATION 12.05
Body Mass Index (BMI)	31.60 kg/m^2 STANDARD_DEVIATION 8.061
Clinical Global Impression - Severity scale (CGI-S) score	3.3 scores on a scale STANDARD_DEVIATION 1.21
Hamilton Anxiety Scale (HAM-A) total score	11.6 scores on a scale STANDARD_DEVIATION 6.65
Height	167.44 cm STANDARD_DEVIATION 9.456
Montgomery Åsberg Depression Rating Scale (MADRS) total score	20.0 scores on a scale STANDARD_DEVIATION 10.7
Race/Ethnicity, Customized American Indian/Alaska Native	5 participants
Race/Ethnicity, Customized Asian	7 participants
Race/Ethnicity, Customized Black/African American	249 participants
Race/Ethnicity, Customized Caucasian (or White, including Hispanic)	813 participants
Race/Ethnicity, Customized Hispanic or Latino	104 participants
Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander	1 participants
Race/Ethnicity, Customized Non-Hispanic and Non-Latino	971 participants
Sex: Female, Male Female	790 Participants
Sex: Female, Male Male	285 Participants
Weight	88.77 kg) STANDARD_DEVIATION 24.16

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	854 / 1,073
serious Total, serious adverse events	29 / 1,073

Outcome results

Primary

Number of Participants With Serious Treatment-Emergent Adverse Events

Serious treatment-emergent adverse events (serious-TEAE) are adverse events with an onset that occurs after receiving study drug and within 30 days after receiving the last dose of study drug. A serious-TEAE may also be a pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug that increases in severity after the start of dosing. Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered serious adverse events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.

Time frame: Over the 52 week period

Population: Safety set

Arm	Measure	Value (NUMBER)
Vortioxetine	Number of Participants With Serious Treatment-Emergent Adverse Events	29 participants

Primary

Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%

Treatment-emergent adverse events (TEAE) are adverse events with an onset that occurs after receiving study drug and within 30 days after receiving the last dose of study drug. A TEAE may also be a pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug that increases in severity after the start of dosing.

Time frame: Over the 52 week period

Population: Safety set

Arm	Measure	Group	Value (NUMBER)
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Nausea	258 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Diarrhea	80 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Vomiting	68 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Constipation	65 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Nasopharyngitis	68 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Viral upper respiratory tract infection	66 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Upper respiratory tract infection	60 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Weight increased	65 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Headache	136 participants
Vortioxetine	Number of Participants With Treatment-Emergent Adverse Events at a Frequency Threshold of ≥5%	Insomnia	56 participants

Primary

Treatment-Emergent Adverse Events Leading to Study Discontinuation

Treatment-emergent adverse events are adverse events with an onset that occurs after receiving study drug and within 30 days after receiving the last dose of study drug. A TEAE may also be a pre-treatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug that increases in severity after the start of dosing.

Time frame: Over the 52 week period

Population: Safety set

Arm	Measure	Value (NUMBER)
Vortioxetine	Treatment-Emergent Adverse Events Leading to Study Discontinuation	117 participants

Secondary

Change From Baseline in Clinical Global Impression Scale-Severity of Illness (CGI-S)

The change between CGI-S score at each assessed visit and CGI-S score at baseline. The CGI-S assesses the clinician's impression of the subject's current state of mental illness and consists of one question for the investigator: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? which is rated on a seven-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=extremely ill). Higher scores indicate greater severity of illness.

Time frame: Baseline and Weeks 4, 24, and 52