Adjunctive Pimavanserin in Subjects With Major Depressive Disorder and Inadequate Response to Antidepressant Treatment

• Sponsor: ACADIA Pharmaceuticals Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03968159
• Collaborator: (none)
• Enrollment: 298
• Locations: 85
• Arms: 2
• Actual Duration (Months): 13.1
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To evaluate the efficacy and safety of adjunctive pimavanserin compared to placebo in subjects with major depressive disorder who have an inadequate response to antidepressant therapy

Condition or Disease	Intervention/Treatment	Phase
Adjunctive Treatment of Major Depressive Disorder	Drug: Pimavanserin; Drug: Placebo	Phase 3

Detailed Description

Two separate studies, idential in design, were planned and initiated under 2 protocol IDs and NCTs, i.e. study ACP-103-54 (NCT03999918) and ACP-103-059 (NCT03968159). In March 2020, recruitment of new patients was paused due to the emerging coronavirus disease 2019 (COVID-19) pandemic. At that point in time, about half of the planned patients had been randomized. The Sponsor decided to combine the 2 identically designed trials, with a prespecified combined statistical analysis plan. As a result, both trials were closed and proceeded with database lock and statistical analysis of the combined data. No further patients were enrolled.

This entry now includes the combined data of studies ACP-103-054 and ACP-103-059.

Study Design

• Study Type: Interventional
• Actual Enrollment: 298 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects With Major Depressive Disorder and Inadequate Response to Antidepressant Treatment (ACP-103-054/059)
• Actual Study Start Date: Apr 25, 2019
• Actual Primary Completion Date: Apr 30, 2020
• Actual Study Completion Date: May 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Drug - pimavanserin Pimavanserin 34 mg tablets	Drug: Pimavanserin; Pimavanserin 34 mg (provided as 2×17 mg tablets) administered orally as a single dose once daily
Placebo Comparator: Placebo Placebo tablets	Drug: Placebo; Placebo (2×placebo tablets [size- and color-matched to pimavanserin]) administered orally as a single dose once daily

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 5 in Hamilton Depression Scale (17 Items) (HAMD-17) Total Score [Baseline, Week 5]

   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. The total score ranging from 0 to 52 will be calculated as the sum of the scores for all 17 items. Higher total scores denote more severe depression.

Secondary Outcome Measures

1. Change From Baseline to Week 5 in Clinical Global Impression-Severity (CGI-S) Score for Depressive Symptoms [Baseline, 5 weeks]

   The CGI-S rates the severity of a subject's depression over the past 7 days and the score ranges from 1 to 7. Higher CGI-S scores denote more severe depression.

2. Change From Baseline to Week 5 in Sheehan Disability Scale (SDS) Score [Baseline, 5 weeks]

   The SDS is a 3-item subject-facing questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. Subjects rate each item using an 11-point scale ranging from 0 (not at all) to 10 (extremely). Higher scores denote greater disability.

3. Change From Baseline to Week 5 in the Changes in Sexual Functioning Questionnaire Short Form [Baseline, 5 weeks]

   The CSFQ-14 is a 14-item version of the CSFQ. This is a patient-facing questionnaire, with a male version and a female version. The total score ranging from 14 to 70 will be calculated as the sum of the scores for all 14 items. Higher total scores denote better sexual functioning.

4. Change From Baseline to Week 5 in Karolinska Sleepiness Scale (KSS) Score [Baseline, 5 weeks]

   The KSS is a scale that measures the subject's drowsiness and is frequently used in studies measuring subjective sleepiness. Scoring is based on a 9-point verbally anchored scale going from "1 = extremely alert" to "9 = very sleepy, great effort to keep awake, fighting sleep". Higher scores denote more drowsiness.

5. Change From Baseline to Week 1 in the HAMD-17 Total Score [Baseline, 1 week]

   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. The total score ranging from 0 to 52 will be calculated as the sum of the scores for all 17 items. Higher total scores denote more severe depression.

6. Treatment Responder and Treatment Remission Rates at Week 5 [Baseline, 5 weeks]

   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. The total score ranging from 0 to 52 will be calculated as the sum of the scores for all 17 items. Treatment response is defined as a reduction from Baseline in HAMD-17 total score of 50% or more. Treatment remission is defined as a HAMD-17 total score ≤7.

7. Change From Baseline to Week 5 in the Hamilton Depression (HAMD) Anxiety/Somatization Factor Score [Baseline, 5 weeks]

   The Anxiety/Somatization factor of the HAMD-17 includes 6 items: psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight. The HAMD-17 Anxiety/Somatization factor score ranging from 0 to 18 will be calculated as the sum of the scores for the 6 items. Higher scores denote more severe anxiety/somatization condition.

8. Change From Baseline to Week 5 in the Barratt Impulsiveness Scale (BIS-11) [Baseline, 5 weeks]

   The BIS-11 is a questionnaire designed to assess the personality/behavioral construct of impulsiveness. It is composed of 30 items describing common impulsive or non-impulsive (reverse scored items: 1, 7, 8, 9, 10, 12, 13, 15, 20, 29, and 30) behaviors and preferences. Items are scored on the following 4-point scale: Rarely/Never = 1; Occasionally = 2; Often = 3; Almost Always/Always = 4. For reverse scored items, a response of 1 is recoded to 4; 2 is recoded to 3; 3 is recoded to 2; and 4 is recoded to 1. The BIS-11 score ranging from 30 to 120 will be calculated as the sum of the scores for all 30 items. Higher scores denote more impulsiveness.

9. Clinical Global Impression-Improvement (CGI-I) Score for Depressive Symptoms at Week 5 [Baseline, 5 weeks]

   The CGI-I rates the change in a subject's depression over the past 7 days relative to the subject's symptoms at Baseline and the score ranges from 1 to 7. Higher CGI-I scores denote less improvement in Depression.

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:

4. Citalopram

5. Escitalopram

6. Paroxetine

7. Fluoxetine

8. Sertraline

9. Duloxetine

10. Venlafaxine

11. Desvenlafaxine

12. Venlafaxine XR

13. Inadequate response to SSRI/SNRI antidepressant treatment is confirmed

14. If the subject is female, she must not be pregnant or breastfeeding. She must also be of non-childbearing potential OR must agree to use acceptable methods of contraception

Exclusion Criteria:

1. Has a history of psychotic disorder or is currently being treated or requires treatment for post-traumatic stress disorder, acute stress disorder, panic disorder, or obsessive compulsive disorder

2. Has current evidence of delirium or an unstable neurological, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies that would affect the patient's ability to participate in the program

3. Has a known history or symptoms of long QT syndrome

4. Is determined to be inappropriate for the study for any reason

Additional inclusion/exclusion criteria apply. 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	University of Alabama at Birmingham (UAB)	Birmingham	Alabama	United States	35233
2	CNS Network	Garden Grove	California	United States	92845
3	Behavioral Research Specialists	Glendale	California	United States	91206
4	Sun Valley Research Center	Imperial	California	United States	92251
5	Irvine Clinical Research	Irvine	California	United States	92614
6	Synergy San Diego	Lemon Grove	California	United States	91945
7	Pacific Research Partners, LLC	Oakland	California	United States	94607
8	NRC Research Institute	Orange	California	United States	92868
9	MCB Clinical Research Centers, LLC	Colorado Springs	Colorado	United States	80910
10	Mountain View Clinical Research, Inc.	Denver	Colorado	United States	80209
11	CT Clinical Research	Cromwell	Connecticut	United States	06416
12	Clinical Neuroscience Solutions ( CNS Healthcare)-Jacksonville	Jacksonville	Florida	United States	32256
13	Meridien Research	Maitland	Florida	United States	32751
14	Florida Research Center, Inc.	Miami	Florida	United States	33174
15	CNS Health Care (Orlando)	Orlando	Florida	United States	32801
16	Emory University School of Medicine	Atlanta	Georgia	United States	30322
17	Synexus Clinical Research	Atlanta	Georgia	United States	30328
18	Great Lakes Clinical Trials	Chicago	Illinois	United States	60640
19	Capstone Clinical Research	Libertyville	Illinois	United States	60048
20	Collective Medical Research, LLC	Prairie Village	Kansas	United States	66208
21	Clinical Trials of America (Monroe, LA)	Monroe	Louisiana	United States	71201
22	Adams Clinical	Watertown	Massachusetts	United States	02472
23	St. Charles Psychiatric Associates-Midwest Research Group	Saint Charles	Missouri	United States	63304
24	Integrative Clinical Trials	Brooklyn	New York	United States	11229
25	Social Psychiatry Research Institute (SPRI)	Brooklyn	New York	United States	11235
26	Mount Sinai Hospital	New York	New York	United States	10029
27	The Medical Research Network, LLC	New York	New York	United States	10128
28	Finger Lake Clinical Research	Rochester	New York	United States	14618
29	Clinical Trial of America, LLC	Hickory	North Carolina	United States	28601
30	Charak Clinical Research Center	Garfield Heights	Ohio	United States	44125
31	Summit Research Network (Oregon) Inc.	Portland	Oregon	United States	97210
32	University Of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
33	Coastal Carolina Research Center	Mount Pleasant	South Carolina	United States	26464
34	Psychiatric Consultants, PC	Franklin	Tennessee	United States	37067
35	Clinical Neuroscience Solutions CNS Healthcare	Memphis	Tennessee	United States	38119
36	Research Strategies of Memphis, LLC	Memphis	Tennessee	United States	38119
37	Future Search Trials of Dallas	Dallas	Texas	United States	75231
38	Baylor College of Medicine	Houston	Texas	United States	77030
39	Clinical Trials of Texas, Inc.	San Antonio	Texas	United States	78229
40	Grayline Research Center	Wichita Falls	Texas	United States	76309
41	IPC Research	Waukesha	Wisconsin	United States	53188
42	ARTES Psykiatrinen Palvelukeskus Oy (Mederon Ltd.)	Helsinki		Finland	00100
43	Savon Psykiatripalvelu Oy	Kuopio		Finland	70110
44	Oulu Mentalcare Oy	Oulu		Finland	90100
45	Satakunnan Psykiatripalvelu Oy at Mehiläinen Pori	Pori		Finland	28130
46	Psykiatri- ja psykologikeskus Mentoria	Tampere		Finland	33200
47	Gabinet Lekarski Psychiatryczny Ireneusz Kaczorowski	Bełchatów		Poland	97-400
48	Przychodnia Śródmieście Sp. z o.o.	Bydgoszcz		Poland	85-080
49	Indywidualna Specijalistyczna Praktyka Lekarska Wiesław Jerzy Cubała	Gdańsk		Poland	80-438
50	Nzop Mentis	Leszno		Poland	64-100
51	Neurologiczny NZOZ im. dr n. med. Hanki	Plewiska		Poland	62-064
52	Zachodniopomorski Instytut Psychoterapii	Szczecin		Poland	70-480
53	Mental Health Research Center, Department #6	Moscow		Russian Federation	115522
54	St. Nicholas the Wonder Worker Psychiatric Hospital	Saint Petersburg		Russian Federation	190121
55	Psychoneurological Dispensary # 5	Saint Petersburg		Russian Federation	195176
56	City Narcology Hospital	Saint Petersburg		Russian Federation	199004
57	Samara Psychiatric Hospital	Samara		Russian Federation	443016
58	Saratov City Clinical Hospital # 2 n.a. V.I. Razumovsky	Saratov		Russian Federation	410028
59	Regional Clinical Psychiatric Hospital of St. Sofia	Saratov		Russian Federation	410060
60	LION-MED	Voronezh		Russian Federation	394052
61	Clinical Center of Serbia, Clinic for psychiatry	Belgrade		Serbia	11000
62	Clinical Hospital Center Dr Dragisa Misovic	Belgrade		Serbia	11000
63	Special hospital for psychiatric diseases "Kovin"	Kovin		Serbia	26220
64	Clinical Center Kragujevac , Clinic for Psychiatry	Kragujevac		Serbia	34000
65	Clinical Center Kragujevac	Kragujevac		Serbia	34000
66	Centre for Mental Health Protection, Clinical Center Nis	Niš		Serbia	18000
67	Clinical Centre Nis, Clinic for Psychiatry Gornja	Toponica		Serbia	18202
68	EPAMED s r.o.	Košice		Slovakia	040 17
69	Liptovska nemocnice s poliklinikou MUDr. Ivana Stodolu, Psychiatricke oddelenie	Liptovský Mikuláš		Slovakia	031 23
70	Centrum Zdravia R.B.K., s.r.o.	Svidník		Slovakia	089 01
71	Cape Trial Centre	Cape Town		South Africa	7530
72	Dr DG Dennis Incorporated Knighton Surgery	Cape Town		South Africa	7708
73	Flexivest Fourteen Research Centre, Unit 1, Durbanville Health Center	Durbanville		South Africa	7550
74	Dr GP Bosch Clinical Research	Pretoria		South Africa	0081
75	Regional Centre of Psychosomatic Disorders based on Psychoneurology Department, Communal Institution "Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnykov	Dnipro		Ukraine	49005
76	Institute of neurology, Psychiatry and Narcology of NAMS of Ukraine, MC "Neuron"	Kharkiv		Ukraine	61091
77	Kyiv Railway Clinical Hospital № 1 of Branch "Health Center" of the Public joint stock company "Ukrainian Railway"	Kyiv		Ukraine	01030
78	Odesa Regional Medical Centre of Mental Health	Odesa		Ukraine	65006
79	Kherson Regional Psychiatric Hospital Department # 3 and # 10 Kherson region	Stepanivka		Ukraine	73488
80	Ternopil Regional Communal Clinical Psychoneurological Hospital, psychiatric department # 2 (men), psychiatric department # 6 (women), Ternopil State Medical University n.a. I.Y. Gorbachevskyy, Chair of Psychiatry, Narcology and Medical Psychology	Ternopil'		Ukraine	46027
81	Communal Institution "Vinnytsia Regional Psychoneurological Hospital n.a. Acad. O.I.Yushchenko", Department #7 (male), Department #10 (female),Vinnytsia National Medical University n.a. M.I.Pyrogov, Department of Psychiatry, Narcology and Psychotherapeuti	Vinnytsia		Ukraine	21005
82	Municipal Institution "Vinnytsya Regional Psychoneurological Hospital n.a. Acad. O.I.Yushchenko", Male Department #14, Female Department #15, Vinnytsya National Medical University n.a. M.I.Pyrogov, Department of Psychiatry, Narcology and Psychotherapeutic	Vinnytsia		Ukraine	21005
83	MAC Clinical Research - Blackpool	Blackpool		United Kingdom	FY2 0JH
84	MAC Clinical Research Ltd - Liverpool	Liverpool		United Kingdom	L34 1BH
85	MAC Clinical Research - Manchester	Manchester		United Kingdom	M13 9NQ

Sponsors and Collaborators

• ACADIA Pharmaceuticals Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol: Study ACP-103-059 protocol (NCT03968159) - Jun 21, 2020
• Study Protocol: Study ACP-103-054 protocol (NCT03999918) - Jun 21, 2020
• Statistical Analysis Plan - Jun 22, 2020

More Information

Publications

None provided.

• Responsible Party: ACADIA Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT03968159
• Other Study ID Numbers: ACP-103-054/059; 2018-003251-37; NCT03999918
• First Posted: May 30, 2019
• Last Update Posted: Nov 17, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Pimavanserin

Study Results

Participant Flow

Recruitment Details	The study was performed in patients with with major depressive disorder who had an inadequate response to antidepressant treatment.
Pre-assignment Detail	During the screening period, patients were assessed for study eligibility, and prohibited medications were discontinued when medically appropriate.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Period Title: Overall Study
STARTED	148	150
COMPLETED	135	135
NOT COMPLETED	13	15

Baseline Characteristics

Arm/Group Title	Pimavanserin	Placebo	Total
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily	Total of all reporting groups
Overall Participants	148	150	298
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.2 (13.45)	44.5 (14.92)	45.8 (14.25)
Sex: Female, Male (Count of Participants)
Female	96 64.9%	112 74.7%	208 69.8%
Male	52 35.1%	38 25.3%	90 30.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.7%	0 0%	1 0.3%
Asian	1 0.7%	2 1.3%	3 1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 4.1%	8 5.3%	14 4.7%
White	137 92.6%	137 91.3%	274 91.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 2%	3 2%	6 2%
Region of Enrollment (participants) [Number]
United States	74 50%	74 49.3%	148 49.7%
Finland	3 2%	9 6%	12 4%
Poland	12 8.1%	6 4%	18 6%
Russia	18 12.2%	12 8%	30 10.1%
Serbia	9 6.1%	8 5.3%	17 5.7%
Slovakia	4 2.7%	3 2%	7 2.3%
South Africa	1 0.7%	1 0.7%	2 0.7%
Ukraine	14 9.5%	16 10.7%	30 10.1%
United Kingdom	13 8.8%	21 14%	34 11.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 5 in Hamilton Depression Scale (17 Items) (HAMD-17) Total Score
Description	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. The total score ranging from 0 to 52 will be calculated as the sum of the scores for all 17 items. Higher total scores denote more severe depression.
Time Frame	Baseline, Week 5

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	-9.0 (0.58)	-8.1 (0.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pimavanserin, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2956
	Comments
	Method	Mixed-effects model for repeated measure
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -2.5 to 0.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.82
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 5 in Clinical Global Impression-Severity (CGI-S) Score for Depressive Symptoms
Description	The CGI-S rates the severity of a subject's depression over the past 7 days and the score ranges from 1 to 7. Higher CGI-S scores denote more severe depression.
Time Frame	Baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	-1.4 (0.10)	-1.1 (0.10)

3. Secondary Outcome

Title	Change From Baseline to Week 5 in Sheehan Disability Scale (SDS) Score
Description	The SDS is a 3-item subject-facing questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. Subjects rate each item using an 11-point scale ranging from 0 (not at all) to 10 (extremely). Higher scores denote greater disability.
Time Frame	Baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	-2.5 (0.22)	-2.1 (0.22)

4. Secondary Outcome

Title	Change From Baseline to Week 5 in the Changes in Sexual Functioning Questionnaire Short Form
Description	The CSFQ-14 is a 14-item version of the CSFQ. This is a patient-facing questionnaire, with a male version and a female version. The total score ranging from 14 to 70 will be calculated as the sum of the scores for all 14 items. Higher total scores denote better sexual functioning.
Time Frame	Baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	3.4 (0.66)	2.5 (0.66)

5. Secondary Outcome

Title	Change From Baseline to Week 5 in Karolinska Sleepiness Scale (KSS) Score
Description	The KSS is a scale that measures the subject's drowsiness and is frequently used in studies measuring subjective sleepiness. Scoring is based on a 9-point verbally anchored scale going from "1 = extremely alert" to "9 = very sleepy, great effort to keep awake, fighting sleep". Higher scores denote more drowsiness.
Time Frame	Baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	-1.4 (0.15)	-0.8 (0.15)

6. Secondary Outcome

Title	Change From Baseline to Week 1 in the HAMD-17 Total Score
Description	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. The total score ranging from 0 to 52 will be calculated as the sum of the scores for all 17 items. Higher total scores denote more severe depression.
Time Frame	Baseline, 1 week

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	-3.8 (0.34)	-3.2 (0.34)

7. Secondary Outcome

Title	Treatment Responder and Treatment Remission Rates at Week 5
Description	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. The total score ranging from 0 to 52 will be calculated as the sum of the scores for all 17 items. Treatment response is defined as a reduction from Baseline in HAMD-17 total score of 50% or more. Treatment remission is defined as a HAMD-17 total score ≤7.
Time Frame	Baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Responder	46 31.1%	46 30.7%
Remitter	27 18.2%	25 16.7%

8. Secondary Outcome

Title	Change From Baseline to Week 5 in the Hamilton Depression (HAMD) Anxiety/Somatization Factor Score
Description	The Anxiety/Somatization factor of the HAMD-17 includes 6 items: psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight. The HAMD-17 Anxiety/Somatization factor score ranging from 0 to 18 will be calculated as the sum of the scores for the 6 items. Higher scores denote more severe anxiety/somatization condition.
Time Frame	Baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	-2.5 (0.21)	-2.5 (0.21)

9. Secondary Outcome

Title	Change From Baseline to Week 5 in the Barratt Impulsiveness Scale (BIS-11)
Description	The BIS-11 is a questionnaire designed to assess the personality/behavioral construct of impulsiveness. It is composed of 30 items describing common impulsive or non-impulsive (reverse scored items: 1, 7, 8, 9, 10, 12, 13, 15, 20, 29, and 30) behaviors and preferences. Items are scored on the following 4-point scale: Rarely/Never = 1; Occasionally = 2; Often = 3; Almost Always/Always = 4. For reverse scored items, a response of 1 is recoded to 4; 2 is recoded to 3; 3 is recoded to 2; and 4 is recoded to 1. The BIS-11 score ranging from 30 to 120 will be calculated as the sum of the scores for all 30 items. Higher scores denote more impulsiveness.
Time Frame	Baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	-3.0 (0.64)	-2.5 (0.64)

10. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I) Score for Depressive Symptoms at Week 5
Description	The CGI-I rates the change in a subject's depression over the past 7 days relative to the subject's symptoms at Baseline and the score ranges from 1 to 7. Higher CGI-I scores denote less improvement in Depression.
Time Frame	Baseline, 5 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all subjects who were randomized, received at least one dose of study drug, and had a baseline value and at least one postbaseline value for HAMD-17 total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily	Placebo tablets administered orally as a single dose once daily
Measure Participants	148	149
Least Squares Mean (Standard Error) [score on a scale]	2.7 (0.09)	2.9 (0.09)

Adverse Events

Time Frame	Adverse Events (AEs) were to be documented through 30 days after the last planned dose in the study which was to be administered at Week 6.
Arm/Group Title	Pimavanserin		Placebo
Arm/Group Description	Pimavanserin 34 mg administered orally as a single dose once daily		Placebo tablets administered orally as a single dose once daily
All Cause Mortality
	Pimavanserin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/148 (0%)		0/150 (0%)
Serious Adverse Events
	Pimavanserin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/148 (1.4%)		2/150 (1.3%)
Cardiac disorders
Atrial fibrillation	1/148 (0.7%)	1	0/150 (0%)	0
Gastrointestinal disorders
Lower gastrointestinal haemorrhage	1/148 (0.7%)	1	0/150 (0%)	0
Gastritis haemorrhagic	0/148 (0%)	0	1/150 (0.7%)	1
Nervous system disorders
Multiple sclerosis	0/148 (0%)	0	1/150 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Pimavanserin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/148 (36.5%)		43/150 (28.7%)
Gastrointestinal disorders
Diarrhoea	12/148 (8.1%)	16	4/150 (2.7%)	4
Dry mouth	11/148 (7.4%)	11	4/150 (2.7%)	5
Infections and infestations
Nasopharyngitis	5/148 (3.4%)	5	9/150 (6%)	9
Nervous system disorders
Headache	31/148 (20.9%)	49	27/150 (18%)	39

Limitations/Caveats

In March 2020, recruitment of new patients was paused due to the emerging coronavirus disease 2019 (COVID-19) pandemic. At that point in time, about half of the planned patients had been randomized. The Sponsor decided to combine this trial with the identically designed trial ACP-103-054, with a prespecified combined statistical analysis plan. As a result, both trials were closed and proceeded with database lock and statistical analysis of the combined data. No further patients were enrolled.

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.