Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Major Depressive Disorder (CLARITY)

• Sponsor: ACADIA Pharmaceuticals Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03018340
• Collaborator: (none)
• Enrollment: 207
• Locations: 36
• Arms: 2
• Actual Duration (Months): 22
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To assess the efficacy of pimavanserin compared to placebo when given adjunctively to a selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant as treatment of patients with Major Depressive Disorder (MDD) and an inadequate response to antidepressant therapy

Condition or Disease	Intervention/Treatment	Phase
Adjunctive Treatment of Major Depressive Disorder	Drug: Pimavanserin; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 207 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Major Depressive Disorder
• Actual Study Start Date: Dec 1, 2016
• Actual Primary Completion Date: Sep 1, 2018
• Actual Study Completion Date: Oct 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pimavanserin 34 mg + SSRI/SNRI Drug- pimavanserin, 34 mg, taken as two 17 mg tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Drug: Pimavanserin; Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Placebo Comparator: Placebo + SSRI/SNRI Placebo, taken as two tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Other: Placebo; Placebo, taken as two tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 5 in the HAMD-17 Total Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Hamilton Rating Scale for Depression (HAMD-17) is a 17-item scale to assess depression. The HAMD-17 consists of 8 items with a score on a 3 point scale and 9 items with a score on a 5 point scale. Each item is rated from least (0) to most frequent or most severe, as applicable, with highest scores of 2 to 4, depending on the item. Items are summed up to calculate the HAMD-17 total score. The total score ranges from 0 to 52. A higher total score indicates more severe depression.

Secondary Outcome Measures

1. Change From Baseline to Week 5 in the SDS Total Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Sheehan Disability Scale is a 3-item patient-facing questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. All items are rated on an 11-point scale from 0 (no impairment) to 10 (most severe). The total SDS score ranges from 0 to 10. It is calculated as the arithmetic mean of the scores for all 3 items. A higher score indicates greater disability.

2. Treatment Response and Remission Rates at the End of 5-week Treatment Period [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Hamilton Rating Scale for Depression (HAMD-17) is a 17-item scale to assess depression. Each item is rated from least (0) to most frequent or most severe, as applicable, with highest scores of 2 to 4 depending on the item. Items are summed up to calculate the HAMD-17 total score. A higher total score indicates more severe depression. Treatment response was defined as a reduction from Baseline in HAMD-17 total score of >=50%. Remission was defined as a HAMD-17 total score <=7.

3. Change From Baseline to Week 5 in CGI-S Total Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Clinical Global Impression-Severity Scale is a 1-item scale, used to rate the severity of the disorder from 0 (not assessed) to 7 (among the most extremely ill patients). A higher CGI-I score denotes more severe depression.

4. CGI-I Score at Week 5 [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Clinical Global Impression- Improvement scale is a 1-item scale, used to rate the global improvement of the patient since beginning of the study from 0 (not assessed) to 7 (very much worse). A higher CGI-I score denotes less improvement in depression.

5. Change From Baseline to Week 5 in SF-12 Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The 12-Item Short Form Health Survey is a patient-reported outcome measure that addresses 8 domains of physical functioning, role - physical, bodily pain, general health perceptions, vitality, social functioning, role - emotional, and mental health. Composite scores were obtained representing physical health and mental health composite summaries, Physical Component Summary (PCS) and Mental Component Summary (MCS), respectively. An algorithm was used to generate PCS and MCS for comparison to normative data. In normative data, the mean score was set to 50; thus, scores >50 indicate better physical or mental health than the mean and scores <50 indicate worse health. A higher score is indicative of a better health state.

6. Change From Baseline to Week 5 in DAI-10 Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Drug Attitude Inventory-10 is a 6-item patient-facing questionnaire to evaluate a patient's perceptions and experiences of treatment. It contains 6 items that a patient who is fully adherent to prescribed medication would answer as "True," and 4 items that a patient who is fully adherent would rate as "False." Scores are allocated to each answer and the total score is calculated as the sum. A correct answer is scored +1 and an incorrect answer is scored -1. The total score ranges from -10 to 10 and is the sum of pluses and minuses. A positive total score indicates a positive subjective response (adherent) and a negative total score indicates a negative subjective response (nonadherent). Higher scores denoted better adherence.

7. Change From Baseline to Week 5 in KSS Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Karolinska Sleepiness Scale is a patient-facing 1-item scale that measures the patient's drowsiness. Scoring is based on a 9-point verbally anchored scale ranging from "extremely alert" (1) to "very sleepy, great effort to keep awake, fighting sleep" (9). Higher scores denote more drowsiness.

8. Change From Baseline to Week 5 in MGH-SFI Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Massachusetts General Hospital Sexual Functioning Index is a patient-facing questionnaire that quantifies sexual dysfunction into 5 functional domains ("interest in sex," "sexual arousal," "ability to achieve orgasm," "ability to maintain erection" [males only], and "sexual satisfaction"). Patients rate each item using a 6-point scale ranging from 1 (good function) to 6 (poor function). The MGH-SFI score is calculated as the arithmetic mean of the item scores for the 5 domains. The mean MGH-SFI score ranges from a minimum value of 1 to a maximum value of 6. Higher scores denotes worse sexual dysfunction.

9. Change From Baseline to Week 5 in BIS-11 Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

   The Barratt Impulsiveness Scale-11 is a questionnaire for assessment of the personality/behavioral construct of impulsiveness. It is composed of 30 items describing common impulsive or non-impulsive (for reverse scored items) behaviors and preferences. Items are scored on a 4-point scale from Rarely/Never (1) to Almost Always/Always (4). Items are summed up to calculate the total score. The BIS-11 total score ranges from 30 to 120. Higher scores denotes more impulsiveness.

10. Change From Baseline to Week 5 in SIS Score [Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively]

    The Sheehan Irritability Scale is a 7-item patient-reported outcome measure to measure the frequency, severity, and impairment associated with irritability in psychiatric patients. It includes items on: irritability, frustration, edginess/ impatience/ overreaction, moodiness, anger with self, anger with others, and temper. Items are answered on an 11-point rating scale where higher scores indicated greater severity (0=not at all, 10=extremely). Item responses are summed into a total score (range=0-70). Higher scores mean higher irritability.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adult patients, aged 18 years and above

2. A clinical diagnosis of major depressive disorder (MDD)

3. Is being treated with one of the following SSRI or SNRI antidepressants as monotherapy:

• Citalopram

• Escitalopram

• Paroxetine

• Fluoxetine

• Sertraline

• Duloxetine

• Venlafaxine

• Desvenlafaxine

• Venlafaxine XR

1. Has a history of inadequate response to antidepressant treatments

Exclusion Criteria:

1. Patient has a psychotic disorder other than MDD

2. Patient has current evidence of a serious and/or unstable neurologic, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies, which would affect the patient's ability to participate in the program

3. Patient has a history or symptoms of long QT syndrome

Patients will be evaluated at screening to ensure that all criteria for study participation are met. Patients may be excluded from the study based on these assessments (and specifically if it is determined that their baseline health and psychiatric condition do not meet all pre-specified entry criteria).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB	Birmingham	Alabama	United States	35294
2	Woodland Research Northwest	Rogers	Arkansas	United States	72758
3	Collaborative Neuroscience Network, LLC	Garden Grove	California	United States	92845
4	Synergy San Diego	National City	California	United States	91950
5	Pacific Research Partners, LLC	Oakland	California	United States	94607
6	Schuster Medical Research Institute	Sherman Oaks	California	United States	91403
7	Viking Clinical Research	Temecula	California	United States	92591
8	Collaborative Neuroscience Network, LLC	Torrance	California	United States	90502
9	Pacific Clinical Research Medical Group	Upland	California	United States	91786
10	Meridien Research	Bradenton	Florida	United States	34201
11	CNS Health care (Jacksonville)	Jacksonville	Florida	United States	32256
12	Meridien Research	Maitland	Florida	United States	32751
13	CNS Health care (Orlando)	Orlando	Florida	United States	32801
14	Emory University School of Medicine	Atlanta	Georgia	United States	30329
15	iResearch Atlanta	Decatur	Georgia	United States	30030
16	Alam Medical Research, INC	Chicago	Illinois	United States	60612
17	Alexian Brothers Center for Psychiatric Research	Hoffman Estates	Illinois	United States	60169
18	KUMC	Wichita	Kansas	United States	67214
19	St. Louis Clinical Trials	Saint Louis	Missouri	United States	63141
20	Altea Research	Las Vegas	Nevada	United States	89102
21	Hassman Research Institute	Berlin	New Jersey	United States	08009
22	Manhattan Behavioral Medicine	New York	New York	United States	10036
23	Finger Lakes Clinical Research	Rochester	New York	United States	14618
24	Neuro-Behavioral Clinical Research	Canton	Ohio	United States	44718
25	IPS Research	Oklahoma City	Oklahoma	United States	73103
26	Rivus Wellness & Research Institute	Oklahoma City	Oklahoma	United States	73112
27	Summit Research Network (Oregon)	Portland	Oregon	United States	97210
28	UPenn	Philadelphia	Pennsylvania	United States	19104
29	BTC of Lincoln	Lincoln	Rhode Island	United States	02865
30	Carolina Clinical Trials, Inc.	Charleston	South Carolina	United States	29407
31	FutureSearch Trials of Dallas, L.P.	Dallas	Texas	United States	75231
32	UTSW	Dallas	Texas	United States	75235
33	Baylor College of Medicine	Houston	Texas	United States	77030
34	Pillar Clinical Research	Richardson	Texas	United States	75080
35	Ericksen Research & Development	Clinton	Utah	United States	84015
36	IPC Research	Waukesha	Wisconsin	United States	53188

Sponsors and Collaborators

• ACADIA Pharmaceuticals Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 26, 2017
• Statistical Analysis Plan - Aug 21, 2018

More Information

Publications

None provided.

• Responsible Party: ACADIA Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT03018340
• Other Study ID Numbers: ACP-103-042
• First Posted: Jan 12, 2017
• Last Update Posted: Nov 14, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Pimavanserin

Study Results

Participant Flow

Pre-assignment Detail	In Stage 1, pts were randomized to pimavanserin or placebo (1:3). At the end of Stage 1, placebo pts not responding to treatment were rerandomized (1:1) in Stage 2; all other pts continued in Stage 2 the initial randomized treatment.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI	Placebo + SSRI/SNRI
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Period Title: Overall Study
STARTED	52	155
COMPLETED	44	125
NOT COMPLETED	8	30

Baseline Characteristics

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI	Placebo + SSRI/SNRI	Total
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Total of all reporting groups
Overall Participants	52	155	207
Age, Customized (Count of Participants)
18-40 years	14 26.9%	55 35.5%	69 33.3%
>40 years	38 73.1%	100 64.5%	138 66.7%
Sex: Female, Male (Count of Participants)
Female	43 82.7%	108 69.7%	151 72.9%
Male	9 17.3%	47 30.3%	56 27.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.9%	3 1.9%	4 1.9%
Asian	0 0%	7 4.5%	7 3.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	9 17.3%	31 20%	40 19.3%
White	38 73.1%	111 71.6%	149 72%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	4 7.7%	3 1.9%	7 3.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 5 in the HAMD-17 Total Score
Description	The Hamilton Rating Scale for Depression (HAMD-17) is a 17-item scale to assess depression. The HAMD-17 consists of 8 items with a score on a 3 point scale and 9 items with a score on a 5 point scale. Each item is rated from least (0) to most frequent or most severe, as applicable, with highest scores of 2 to 4, depending on the item. Items are summed up to calculate the HAMD-17 total score. The total score ranges from 0 to 52. A higher total score indicates more severe depression.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

FAS Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. FAS Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Baseline (BL)	22.9 (0.62)	22.0 (0.34)	20.3 (0.83)	20.4 (0.79)
Change from BL to Week 5	-11.9 (1.14)	-7.1 (0.55)	-2.8 (0.75)	-3.2 (1.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pimavanserin 34 mg + SSRI/SNRI, Stage 1, Placebo + SSRI/SNRI, Stage 1, Pimavanserin 34 mg + SSRI/SNRI, Stage 2, Placebo + SSRI/SNRI, Stage 2
	Comments	This is the primary statistical comparison for Stage 1 and Stage 2 combined.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0390
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in weighted MMRM LSMs
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -3.4 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.85
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pimavanserin 34 mg + SSRI/SNRI, Stage 1, Placebo + SSRI/SNRI, Stage 1
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in MMRM LSMs
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -6.1 to -1.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.09
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pimavanserin 34 mg + SSRI/SNRI, Stage 2, Placebo + SSRI/SNRI, Stage 2
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6940
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in MMRM LSMs
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -2.1 to 3.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.30
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 5 in the SDS Total Score
Description	The Sheehan Disability Scale is a 3-item patient-facing questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. All items are rated on an 11-point scale from 0 (no impairment) to 10 (most severe). The total SDS score ranges from 0 to 10. It is calculated as the arithmetic mean of the scores for all 3 items. A higher score indicates greater disability.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Basline (BL)	6.365 (0.2996)	6.519 (0.1716)	5.753 (0.3314)	5.747 (0.4191)
Change from BL to Week 5	-3.229 (0.4436)	-2.026 (0.2233)	-0.890 (0.2798)	-0.507 (0.3288)

3. Secondary Outcome

Title	Treatment Response and Remission Rates at the End of 5-week Treatment Period
Description	The Hamilton Rating Scale for Depression (HAMD-17) is a 17-item scale to assess depression. Each item is rated from least (0) to most frequent or most severe, as applicable, with highest scores of 2 to 4 depending on the item. Items are summed up to calculate the HAMD-17 total score. A higher total score indicates more severe depression. Treatment response was defined as a reduction from Baseline in HAMD-17 total score of >=50%. Remission was defined as a HAMD-17 total score <=7.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Treatment responders Week 5	27 51.9%	38 24.5%	2 1%	2 NaN
Remission rate Week 5	12 23.1%	17 11%	1 0.5%	1 NaN

4. Secondary Outcome

Title	Change From Baseline to Week 5 in CGI-S Total Score
Description	The Clinical Global Impression-Severity Scale is a 1-item scale, used to rate the severity of the disorder from 0 (not assessed) to 7 (among the most extremely ill patients). A higher CGI-I score denotes more severe depression.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Baseline (BL)	4.6 (0.09)	4.4 (0.05)	4.1 (0.16)	4.1 (0.14)
Change from BL to Week 5	-2.0 (0.21)	-1.1 (0.10)	-0.5 (0.13)	-0.5 (0.23)

5. Secondary Outcome

Title	CGI-I Score at Week 5
Description	The Clinical Global Impression- Improvement scale is a 1-item scale, used to rate the global improvement of the patient since beginning of the study from 0 (not assessed) to 7 (very much worse). A higher CGI-I score denotes less improvement in depression.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	44	127	29	24
Least Squares Mean (Standard Error) [score on a scale]	2.2 (0.17)	2.8 (0.10)	3.0 (0.18)	3.1 (0.19)

6. Secondary Outcome

Title	Change From Baseline to Week 5 in SF-12 Score
Description	The 12-Item Short Form Health Survey is a patient-reported outcome measure that addresses 8 domains of physical functioning, role - physical, bodily pain, general health perceptions, vitality, social functioning, role - emotional, and mental health. Composite scores were obtained representing physical health and mental health composite summaries, Physical Component Summary (PCS) and Mental Component Summary (MCS), respectively. An algorithm was used to generate PCS and MCS for comparison to normative data. In normative data, the mean score was set to 50; thus, scores >50 indicate better physical or mental health than the mean and scores <50 indicate worse health. A higher score is indicative of a better health state.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	151	29	29
PCS baseline (BL)	49.587 (1.7918)	48.783 (0.9845)	46.945 (2.0961)	48.994 (2.0596)
PCS change from BL to Week 5	-0.981 (1.1036)	-0.726 (0.7095)	-0.546 (1.4718)	1.811 (1.2081)
MCS baseline (BL)	23.113 (1.2848)	24.004 (0.6570)	27.557 (1.4023)	28.524 (1.5909)
MCS change from BL to Week 5	16.146 (1.9531)	7.989 (0.8137)	3.566 (1.5421)	0.578 (1.4600)

7. Secondary Outcome

Title	Change From Baseline to Week 5 in DAI-10 Score
Description	The Drug Attitude Inventory-10 is a 6-item patient-facing questionnaire to evaluate a patient's perceptions and experiences of treatment. It contains 6 items that a patient who is fully adherent to prescribed medication would answer as "True," and 4 items that a patient who is fully adherent would rate as "False." Scores are allocated to each answer and the total score is calculated as the sum. A correct answer is scored +1 and an incorrect answer is scored -1. The total score ranges from -10 to 10 and is the sum of pluses and minuses. A positive total score indicates a positive subjective response (adherent) and a negative total score indicates a negative subjective response (nonadherent). Higher scores denoted better adherence.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Baseline (BL)	4.2 (0.61)	4.4 (0.34)	5.1 (0.68)	4.8 (0.70)
Change from BL to Week 5	1.4 (0.56)	0.5 (0.26)	0.6 (0.66)	0.3 (0.50)

8. Secondary Outcome

Title	Change From Baseline to Week 5 in KSS Score
Description	The Karolinska Sleepiness Scale is a patient-facing 1-item scale that measures the patient's drowsiness. Scoring is based on a 9-point verbally anchored scale ranging from "extremely alert" (1) to "very sleepy, great effort to keep awake, fighting sleep" (9). Higher scores denote more drowsiness.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Baseline (BL)	6.7 (0.19)	6.6 (0.14)	6.7 (0.29)	6.1 (0.30)
Change from BL to Week 5	-1.9 (0.33)	-0.4 (0.18)	-0.5 (0.29)	-0.2 (0.29)

9. Secondary Outcome

Title	Change From Baseline to Week 5 in MGH-SFI Score
Description	The Massachusetts General Hospital Sexual Functioning Index is a patient-facing questionnaire that quantifies sexual dysfunction into 5 functional domains ("interest in sex," "sexual arousal," "ability to achieve orgasm," "ability to maintain erection" [males only], and "sexual satisfaction"). Patients rate each item using a 6-point scale ranging from 1 (good function) to 6 (poor function). The MGH-SFI score is calculated as the arithmetic mean of the item scores for the 5 domains. The mean MGH-SFI score ranges from a minimum value of 1 to a maximum value of 6. Higher scores denotes worse sexual dysfunction.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Baseline (BL)	4.642 (0.1967)	4.457 (0.1176)	4.678 (0.2269)	4.264 (0.2893)
Change from BL to Week 5	-0.830 (0.1814)	-0.155 (0.0807)	-0.472 (0.1580)	-0.183 (0.1085)

10. Secondary Outcome

Title	Change From Baseline to Week 5 in BIS-11 Score
Description	The Barratt Impulsiveness Scale-11 is a questionnaire for assessment of the personality/behavioral construct of impulsiveness. It is composed of 30 items describing common impulsive or non-impulsive (for reverse scored items) behaviors and preferences. Items are scored on a 4-point scale from Rarely/Never (1) to Almost Always/Always (4). Items are summed up to calculate the total score. The BIS-11 total score ranges from 30 to 120. Higher scores denotes more impulsiveness.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Baseline (BL)	72.5 (1.53)	70.0 (0.92)	65.9 (1.79)	70.3 (1.86)
Change from BL to Week 5	-4.2 (1.10)	-2.8 (0.72)	-1.4 (0.87)	1.7 (1.33)

11. Secondary Outcome

Title	Change From Baseline to Week 5 in SIS Score
Description	The Sheehan Irritability Scale is a 7-item patient-reported outcome measure to measure the frequency, severity, and impairment associated with irritability in psychiatric patients. It includes items on: irritability, frustration, edginess/ impatience/ overreaction, moodiness, anger with self, anger with others, and temper. Items are answered on an 11-point rating scale where higher scores indicated greater severity (0=not at all, 10=extremely). Item responses are summed into a total score (range=0-70). Higher scores mean higher irritability.
Time Frame	Baseline, 5 weeks and 10 weeks during Stage 1 and Stage 2, respectively

Outcome Measure Data

Analysis Population Description

Stage 1: pts randomized to Stage 1, received ≥1 dose of study drug in Stage 1, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 1. Stage 2: pts randomized to Stage 2, received ≥1 dose of study drug in Stage 2, and had a baseline value and ≥1 post-baseline value for HAMD-17 total score in Stage 2.

Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1	Placebo + SSRI/SNRI, Stage 1	Pimavanserin 34 mg + SSRI/SNRI, Stage 2	Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.	Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
Measure Participants	51	152	29	29
Baseline (BL)	38.9 (2.04)	38.8 (1.22)	35.2 (2.45)	36.6 (3.19)
Change from BL to Week 5	-19.4 (2.97)	-10.8 (1.42)	-4.8 (2.06)	-6.6 (2.77)

Adverse Events

Time Frame	10 weeks
Adverse Event Reporting Description	Safety analysis set Stage 1: all pts randomized to Stage 1 and received ≥1 dose of study drug in Stage 1 Safety analysis set Stage 2: all pts randomized to Stage 2 and received ≥1 dose of study drug in Stage 2 AEs were summarized for the Safety analysis set Stage 1 (5 weeks) and for the Safety analysis set Stage 2 (5 weeks) separately. Patients in Stage 1 and 2 do not add up, as patients in Stage 2 are a subset of placebo non-responders from Stage 1.
Arm/Group Title	Pimavanserin 34 mg + SSRI/SNRI, Stage 1		Placebo + SSRI/SNRI, Stage 1		Pimavanserin 34 mg + SSRI/SNRI, Stage 2		Placebo + SSRI/SNRI, Stage 2
Arm/Group Description	Patients randomized to Pimavanserin at the beginning of Stage 1. Patients on Pimavanserin remained on their assigned treatment throughout Stage 1 and 2 of the study. Pimavanserin 34 mg (2 x 17 mg), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.		Patients randomized to Placebo at the beginning of Stage 1. This group includes all patients randomized to placebo in Stage 1, irrespective of response in Stage 1 and later rerandomization to Pimavanserin or Placebo in Stage 2. Placebo (2 x Placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.		Patients rerandomized to Pimavanserin 34 mg at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1, who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Pimavanserin 34 mg (2 x 17 mg tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.		Patients rerandomized to Placebo at the beginning of Stage 2. Patients represent a subset of the placebo patients not responding to treatment (by protocol-defined criteria) in Stage 1 who were then randomly assigned (1:1) to pimavanserin or placebo in Stage 2. Placebo (2 x placebo tablets), once daily by mouth. All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.
All Cause Mortality
	Pimavanserin 34 mg + SSRI/SNRI, Stage 1		Placebo + SSRI/SNRI, Stage 1		Pimavanserin 34 mg + SSRI/SNRI, Stage 2		Placebo + SSRI/SNRI, Stage 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/155 (0%)		0/29 (0%)		0/29 (0%)
Serious Adverse Events
	Pimavanserin 34 mg + SSRI/SNRI, Stage 1		Placebo + SSRI/SNRI, Stage 1		Pimavanserin 34 mg + SSRI/SNRI, Stage 2		Placebo + SSRI/SNRI, Stage 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/52 (1.9%)		1/155 (0.6%)		0/29 (0%)		0/29 (0%)
Cardiac disorders
Acute myocardial infarction	1/52 (1.9%)	1	0/155 (0%)	0	0/29 (0%)	0	0/29 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	0/52 (0%)	0	1/155 (0.6%)	1	0/29 (0%)	0	0/29 (0%)	0
Renal and urinary disorders
Calculus bladder	0/52 (0%)	0	1/155 (0.6%)	1	0/29 (0%)	0	0/29 (0%)	0
Other (Not Including Serious) Adverse Events
	Pimavanserin 34 mg + SSRI/SNRI, Stage 1		Placebo + SSRI/SNRI, Stage 1		Pimavanserin 34 mg + SSRI/SNRI, Stage 2		Placebo + SSRI/SNRI, Stage 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/52 (42.3%)		36/155 (23.2%)		6/29 (20.7%)		0/29 (0%)
Gastrointestinal disorders
Dry mouth	5/52 (9.6%)	5	4/155 (2.6%)	4	0/29 (0%)	0	0/29 (0%)	0
Nausea	5/52 (9.6%)	5	7/155 (4.5%)	7	0/29 (0%)	0	0/29 (0%)	0
Infections and infestations
Sinusitis	3/52 (5.8%)	3	0/155 (0%)	0	2/29 (6.9%)	2	0/29 (0%)	0
Upper respiratory tract infection	3/52 (5.8%)	3	7/155 (4.5%)	8	2/29 (6.9%)	2	0/29 (0%)	0
Urinary tract infection	3/52 (5.8%)	4	1/155 (0.6%)	1	0/29 (0%)	0	0/29 (0%)	0
Metabolism and nutrition disorders
Increased appetite	3/52 (5.8%)	3	0/155 (0%)	0	0/29 (0%)	0	0/29 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/52 (0%)	0	0/155 (0%)	0	2/29 (6.9%)	2	0/29 (0%)	0
Nervous system disorders
Headache	5/52 (9.6%)	5	14/155 (9%)	15	0/29 (0%)	0	0/29 (0%)	0
Dizziness	4/52 (7.7%)	4	9/155 (5.8%)	9	0/29 (0%)	0	0/29 (0%)	0
Sedation	4/52 (7.7%)	4	4/155 (2.6%)	4	0/29 (0%)	0	0/29 (0%)	0

Limitations/Caveats

Interpretation of Stage 2 results is limited by the reduced number of patients vs initial projections anticipated by the protocol.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigator may publish the study results, relative to their own patients, only after review, comment and approval by the sponsor. No publication of confidential information shall be made without the sponsor's prior written consent. At least 60 days prior to submitting a manuscript or prior to any public presentation, a copy of the manuscript or presentation will be provided to the Sponsor for review and comment. The sponsor has 60 days to review and comment.