Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia (ENHANCE-1)

• ClinicalTrials.gov Identifier: NCT02970292
• Recruitment Status: Completed
• First Posted: November 22, 2016
• Results First Posted: June 17, 2020
• Last Update Posted: June 17, 2020
• Sponsor: ACADIA Pharmaceuticals Inc.
• Information provided by (Responsible Party): ACADIA Pharmaceuticals Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Schizophrenia
• Interventions: Drug: Pimavanserin; Drug: Placebo
• Enrollment: 396

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description	Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Period Title: Overall Study
Started	198	198
Completed	174	190
Not Completed	24	8
Reason Not Completed
Physician Decision	1	1
Withdrawal by Subject	11	5
Noncompliance with study drug	2	2
Adverse Event	5	0
Lack of Efficacy	1	0
Lost to Follow-up	1	0
Protocol Violation	2	0
Other	1	0

Baseline Characteristics

Arm/Group Title		Pimavanserin	Placebo	Total
Arm/Group Description		Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.	Total of all reporting groups
Overall Number of Baseline Participants		198	198	396
Baseline Analysis Population Description		All patients randomised and treated with at least 1 dose of study drug
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	198 participants	198 participants	396 participants
		36.8 (9.42)	37.4 (9.45)	37.1 (9.43)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	198 participants	198 participants	396 participants
	Female	72 36.4%	78 39.4%	150 37.9%
	Male	126 63.6%	120 60.6%	246 62.1%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	198 participants	198 participants	396 participants
	American Indian or Alaska Native	0 0.0%	1 0.5%	1 0.3%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	22 11.1%	22 11.1%	44 11.1%
	White	176 88.9%	172 86.9%	348 87.9%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	3 1.5%	3 0.8%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	198 participants	198 participants	396 participants
Canada		0	2	2
Hungary		3	3	6
United States		37	34	71
Czechia		1	1	2
Ukraine		16	24	40
Poland		3	3	6
Bulgaria		43	50	93
Lithuania		3	6	9
Serbia		44	33	77
Russia		48	42	90
BMI; Mean (Standard Deviation); Unit of measure: Kg/m2
	Number Analyzed	198 participants	198 participants	396 participants
		26.74 (4.177)	26.92 (4.029)	26.83 (4.099)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) Total Score
Description	The PANSS is a 30-item scale used to evaluate the presence, absence, and severity of schizophrenia symptoms. The 30 items are arranged as 7 positive symptom items (P1 to P7), 7 negative symptom items (N1 to N7), and 16 general psychopathology symptom items (G1 to G16). Items are scored over the past week (7 days) on a 7-point scale ranging from 1 (absent) to 7 (extreme). The PANSS total score can range from a minimum of 30 to a maximum of 210, where a higher score signifies greater severity of schizophrenia symptoms.
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title		Pimavanserin	Placebo
Arm/Group Description:		Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed		193	196
Mean (Standard Error); Unit of Measure: score on a scale
Baseline	Number Analyzed	193 participants	196 participants
		88.3 (0.68)	88.1 (0.61)
Change from baseline to Week 6	Number Analyzed	173 participants	189 participants
		-15.3 (0.93)	-13.4 (0.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pimavanserin, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0940
	Comments	[Not Specified]
	Method	mixed-effects model for repeated measure
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in MMRM LSMs
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -4.5 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.24
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Change From Baseline to Week 6 in the Clinical Global Impression-Severity (CGI-S) Score
Description	The CGI-S 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-S score denotes greater severity of the disorder.
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title		Pimavanserin	Placebo
Arm/Group Description:		Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed		193	196
Mean (Standard Error); Unit of Measure: score on a scale
Baseline	Number Analyzed	193 participants	196 participants
		4.6 (0.04)	4.6 (0.04)
Change from baseline to Week 6	Number Analyzed	173 participants	189 participants
		-0.8 (0.06)	-0.7 (0.05)

3. Secondary Outcome

Title	Change From Baseline (CFBL) to Week 6 in PANSS Subscale Scores, i.e. PANSS Positive Subscale Score, PANSS Negative Subscale Score and PANSS General Psychopathological Scale Score
Description	The PANSS is a 30-item scale used to evaluate the presence, absence, and severity of schizophrenia symptoms. The 30 items are arranged as 7 positive symptom items (P1 to P7), 7 negative symptom items (N1 to N7), and 16 general psychopathology symptom items (G1 to G16). Items are scored over the past week (7 days) on a 7-point scale ranging from 1 (absent) to 7 (extreme). The PANSS positive subscale score can range from 7 to 49; the PANSS negative subscale score can range from 7 to 49; the PANSS general psychopathology scale score can range from 16 to 112. For each of the subscale scores, a higher score signifies greater severity of schizophrenia symptoms.
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title		Pimavanserin	Placebo
Arm/Group Description:		Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed		193	196
Mean (Standard Error); Unit of Measure: score on a scale
PANSS positive scale BL	Number Analyzed	193 participants	196 participants
		23.0 (0.25)	22.8 (0.23)
PANSS positive scale CFBL to 6 weeks	Number Analyzed	173 participants	189 participants
		-5.4 (0.34)	-4.9 (0.30)
PANSS negative scale BL	Number Analyzed	193 participants	196 participants
		23.0 (0.29)	23.1 (0.29)
PANSS negative scale CFBL to 6 weeks	Number Analyzed	173 participants	189 participants
		-2.8 (0.28)	-2.1 (0.28)
PANSS general psychopatholigy scale BL	Number Analyzed	193 participants	196 participants
		42.4 (0.45)	42.2 (0.45)
PANSS gen. psychopath. scale CFBL to 6 w	Number Analyzed	173 participants	189 participants
		-7.2 (0.47)	-6.4 (0.47)

4. Secondary Outcome

Title	PANSS Responders
Description	Porportion of patients showing a PANSS response of >=20% or >=30% reduction in PANSS total score PANSS total score reduction signifies improvement.
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description:	Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed	193	196
Measure Type: Count of Participants; Unit of Measure: Participants
PANSS total score reduction >=20%	109 56.5%	99 50.5%
PANSS total score reduction >=30%	71 36.8%	67 34.2%

5. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I) Response
Description	The CGI-I is a 1-item scale, used to rate the improvement from 1 (very much improved) to 7 (very much worse). Higher scores denote less improvement. A CGI-I score of 1 or 2 was counted as response. The Analysis was performed twice; once including missing values as non-responders (MN) and once including only observed cases (OC).
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title		Pimavanserin	Placebo
Arm/Group Description:		Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed		193	196
Measure Type: Count of Participants; Unit of Measure: Participants
CGI-I response (MN)	Number Analyzed	193 participants	196 participants
		68 35.2%	65 33.2%
CGI-I response (OC)	Number Analyzed	173 participants	189 participants
		68 39.3%	65 34.4%

6. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I) Score at Week 6
Description	The CGI-I is a 1-item scale, used to rate the improvement from 1 (very much improved) to 7 (very much worse). Higher scores denote less improvement.
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title	Pimavanserin	Placebo
Arm/Group Description:	Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed	173	189
Mean (Standard Error); Unit of Measure: score on a scale
	2.8 (0.07)	3.0 (0.07)

7. Secondary Outcome

Title	Change From Baseline to Week 6 in Personal and Social Performance (PSP) Scale Score
Description	The PSP is a validated 100-point (1 to100) single-item rating scale to assess the psychosocial functioning of patients with schizophrenia. The maximum score is 100. Higher scores denote better psychosocial functioning.
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title		Pimavanserin	Placebo
Arm/Group Description:		Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed		193	196
Mean (Standard Error); Unit of Measure: score on a scale
Baseline	Number Analyzed	193 participants	196 participants
		51.8 (0.79)	51.6 (0.78)
Change from baseline to Week 6	Number Analyzed	173 participants	188 participants
		6.8 (0.71)	5.7 (0.64)

8. Secondary Outcome

Title	Drug Attitude Inventory (DAI-10)
Description	The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a patient who is fully adherent to study medication would answer as "True" and 4 items (2, 5, 6, and 8) that a patient who is fully adherent to study medication would answer as "False." A correct answer is scored +1 and an incorrect answer is scored -1; the total score is derived as overall sum. The score can range from -10 to 10. Positive total scores indicate adherence and negative total scores indicate non-adherence. Higher scores denote better adherence.
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title		Pimavanserin	Placebo
Arm/Group Description:		Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed		193	196
Mean (Standard Error); Unit of Measure: score on a scale
Baseline	Number Analyzed	193 participants	196 participants
		5.6 (0.24)	5.8 (0.23)
Change from baseline to Week 6	Number Analyzed	173 participants	188 participants
		0.4 (0.20)	0.4 (0.20)

9. Secondary Outcome

Title	Change From Baseline to Week 6 in Karolinska Sleepiness Scale (KSS) Score
Description	The KSS is a self-reported measure of a patient's level of drowsiness. In this study, drowsiness was to be rated during the last week (7 days). Scoring is based on a 9-point verbally anchored scale ranging from 1 (extremely alert) to 9 (very sleepy, great effort to keep awake, fighting sleep). The maximum score is 9. Higher scores denote more drowsiness.
Time Frame	From baseline to Week 6

Outcome Measure Data

Analysis Population Description

Patients randomised and treated (at least 1 dose of study medication) who had both a baseline value and at least 1 post-baseline value for the PANSS total score.

Arm/Group Title		Pimavanserin	Placebo
Arm/Group Description:		Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.	Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
Overall Number of Participants Analyzed		193	196
Mean (Standard Error); Unit of Measure: score on a scale
Baseline	Number Analyzed	193 participants	196 participants
		4.6 (0.11)	4.7 (0.12)
Change from baseline to Week 6	Number Analyzed	173 participants	189 participants
		-0.5 (0.12)	-0.2 (0.12)

Adverse Events

Time Frame	From baseline to Week 6
Adverse Event Reporting Description	The analysis population were those patients who received at least one dose of the study drug. Patients were classified according to the actual treatment received.
Arm/Group Title	Pimavanserin		Placebo
Arm/Group Description	Patients started treatment with pimavanserin 20 mg once daily (QD). At the Week 1, Week 2 and Week 3 visit, the dose could be increased to 34 mg QD or decreased to 10 mg QD at the investigator's discretion (to improve symptom reliev or tolerability, respectively). Thereafter, the daily dose was to remain the same for the remainder of the study. Patients were to continue their background antipsychotic treatment.		Pimavanserin-matching Placebo. Patients were to continue their background antipsychotic treatment.
All-Cause Mortality
	Pimavanserin		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/198 (0.00%)		0/198 (0.00%)
Serious Adverse Events
	Pimavanserin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/198 (1.01%)		2/198 (1.01%)
Psychiatric disorders
Schizophrenia * 1	1/198 (0.51%)	1	1/198 (0.51%)	1
Hallucination auditory * 1	1/198 (0.51%)	1	0/198 (0.00%)	0
Psychotic symptom * 1	0/198 (0.00%)	0	1/198 (0.51%)	1
Self-injurious ideation * 1	0/198 (0.00%)	0	1/198 (0.51%)	1
Suicidal ideation * 1	1/198 (0.51%)	1	0/198 (0.00%)	0
1 Term from vocabulary, MedDRA 22.0; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pimavanserin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/198 (15.66%)		31/198 (15.66%)
Nervous system disorders
Headache * 1	13/198 (6.57%)	16	18/198 (9.09%)	24
Somnolence * 1	13/198 (6.57%)	19	7/198 (3.54%)	8
Psychiatric disorders
Insomnia * 1	10/198 (5.05%)	10	7/198 (3.54%)	7
1 Term from vocabulary, MedDRA 22.0; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Investigator may publish the study results, relative to his/her 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.

Results Point of Contact

• Name/Title: Sr. Dir. Medical Information and Medical Communications
• Organization: ACADIA Pharmaceuticals Inc.
• Phone: +1-858-261-2897
• EMail: medicalinformation@acadia-pharm.com

• Responsible Party: ACADIA Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT02970292
• Other Study ID Numbers: ACP-103-034; 2016-003434-24 ( EudraCT Number )
• First Submitted: November 18, 2016
• First Posted: November 22, 2016
• Results First Submitted: May 29, 2020
• Results First Posted: June 17, 2020
• Last Update Posted: June 17, 2020