A Study of ALKS 3831 in Adults With Schizophrenia

• Sponsor: Alkermes, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01903837
• Collaborator: (none)
• Enrollment: 347
• Locations: 61
• Arms: 4
• Duration (Months): 21
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a Phase 2, randomized, placebo-controlled multicenter study, which will be conducted in 2 parts. The study duration for each subject will be approximately 33 weeks and will include 25 study visits.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Samidorphan (Low Dose); Drug: Samidorphan (Medium Dose); Drug: Samidorphan (High Dose); Drug: Placebo; Drug: Olanzapine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 347 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Multicenter, Safety, Tolerability, and Dose-Ranging Study of Samidorphan, a Component of ALKS 3831, in Adults With Schizophrenia Treated With Olanzapine
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low Dose Olanzapine + low dose samidorphan tablets taken once daily	Drug: Samidorphan (Low Dose); Tablets taken once daily; Other Names: Low dose samidorphan (ALKS 33) ; Drug: Olanzapine; Tablets taken once daily
Experimental: Medium Dose Olanzapine + medium dose samidorphan tablets taken once daily	Drug: Samidorphan (Medium Dose); Tablets taken once daily; Other Names: Medium dose samidorphan (ALKS 33) ; Drug: Olanzapine; Tablets taken once daily
Experimental: High Dose Olanzapine + high dose samidorphan tablets taken once daily	Drug: Samidorphan (High Dose); Tablets taken once daily; Other Names: High dose samidorphan (ALKS 33) ; Drug: Olanzapine; Tablets taken once daily
Placebo Comparator: Placebo Olanzapine + placebo tablets taken once daily	Drug: Placebo; Tablets taken once daily; Drug: Olanzapine; Tablets taken once daily

Outcome Measures

Primary Outcome Measures

1. Absolute Change in Total Positive and Negative Syndrome Scale (PANSS) Score [Baseline (Day 8) to Day 92 (end of study Part A)]

   Change from baseline (Day 8) to Day 92 (end of study Part A). The PANSS is a 30-item scale measuring severity of schizophrenia symptoms. Symptom severity for each item is rated on a 7-point scale (1 = absent; 7 = extreme), and the total score is added together, with a minimum score of 30 and a maximum score of 210. A higher score indicates more severe symptoms, while a lower score indicates less severe symptoms.

Secondary Outcome Measures

1. Percent Change in Body Weight (Kilogram) From Baseline to Day 92 [Baseline (Day 8) to Day 92 (end of study Part A)]

   Percent change from baseline (Day 8) to the end of Part A (Day 92)

2. Absolute Change in Body Weight (kg) From Baseline to Day 92 [Baseline (Day 8) to Day 92 (end of study Part A)]

   Change from randomization (Day 8) to the end of Part A (Week 12; Day 92)

3. Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 [Baseline (Day 8) to Day 92 (end of study Part A)]

   Significant weight gain will include a >=5%, >= 7%, or >=10% gain in body weight from baseline (Day 8) to Day 92 (end of study Part A)

4. Change in Clinical Global Impressions - Severity (CGI-S) From Baseline to Day 92 [Baseline (Day 8) to Day 92 (end of study Part A)]

   Change in CGI-S score from baseline (Day 8) to the end of Part A (Week 12; Day 92). The CGI-S is a 7-point scale intended to measure the severity of a patient's illness at the time of assessment. Scores range from 1 (normal) to 7(extremely ill), so a higher score is correlative to more severe illness.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18 to 50 years, inclusive

• Body mass index (BMI) of 17-30 kg/m2, inclusive

• Diagnosis of schizophrenia that is clinically stable

Exclusion Criteria:

• Initiated 1st antipsychotic treatment within the past 12 months and/or has had symptoms lasting <2 years

• Current diagnosis of alcohol or drug use disorder, moderate or severe

• Clinically significant or unstable medical illness, condition, or disorder

• Pregnant or breastfeeding

• Significant changes in diet or exercise regimen or plans to join a weight management program during the study

• Opioid medications taken within 14 days and/or need to take opioid medication during the study period

• History of hypersensitivity to or intolerance of olanzapine

• Use of olanzapine, clozapine, mesoridazine, chlorpromazine, or thioridazine for more than 1 week during the past year

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alkermes Investigational Site	Little Rock	Arkansas	United States	72211
2	Alkermes Investigational Site	Anaheim	California	United States	92805
3	Alkermes Investigational Site	Costa Mesa	California	United States	92626
4	Alkermes Investigational Site	Culver City	California	United States	90230
5	Alkermes Investigational Site	Escondido	California	United States	92025
6	Alkermes Investigational Site	Garden Grove	California	United States	92845
7	Alkermes Investigational Site	National City	California	United States	91950
8	Alkermes Investigational Site	Oakland	California	United States	94612
9	Alkermes Investigational Site	Oceanside	California	United States	92056
10	Alkermes Investigational Site	Orange	California	United States	92868
11	Alkermes Investigational Site	Pico Rivera	California	United States	90660
12	Alkermes Investigational Site	San Diego	California	United States	92103
13	Alkermes Investigational Site	Torrance	California	United States	90502
14	Alkermes Investigational Site	New Britain	Connecticut	United States	06052
15	Alkermes Investigational Site	Washington	District of Columbia	United States	20016
16	Alkermes Investigational Site	Bradenton	Florida	United States	34208
17	Alkermes Investigational Site	Fort Lauderdale	Florida	United States	33308
18	Alkermes Investigational Site	Gainesville	Florida	United States	32607
19	Alkermes Investigational Site	Kissimmee	Florida	United States	34741
20	Alkermes Investigational Site	Leesburg	Florida	United States	34748
21	Alkermes Investigational Site	Oakland Park	Florida	United States	33334
22	Alkermes Investigational Site	Orlando	Florida	United States	32810
23	Alkermes Investigational Site	Atlanta	Georgia	United States	30308
24	Alkermes Investigational Site	Decatur	Georgia	United States	30030
25	Alkermes Investigational Site	Chicago	Illinois	United States	60640
26	Alkermes Investigational Site	Lake Charles	Louisiana	United States	70629
27	Alkermes Investigational Site	Shreveport	Louisiana	United States	71101
28	Alkermes Investigational Site	Rockville	Maryland	United States	20850
29	Alkermes Investigational Site	Flowood	Mississippi	United States	39232
30	Alkermes Investigational Site	Creve Coeur	Missouri	United States	63141
31	Alkermes Investigational Site	Saint Louis	Missouri	United States	63118
32	Alkermes Investigational Site	Marlton	New Jersey	United States	08053
33	Alkermes Investigational Site	Neptune	New Jersey	United States	07754
34	Alkermes Investigational Site	Canton	Ohio	United States	44718
35	Alkermes Investigational Site	Mason	Ohio	United States	45040
36	Alkermes Investigational Site	Oklahoma City	Oklahoma	United States	73103
37	Alkermes Investigational Site	Oklahoma City	Oklahoma	United States	73116
38	Alkermes Investigational Site	Philadelphia	Pennsylvania	United States	19139
39	Alkermes Investigational Site	Charleston	South Carolina	United States	29407
40	Alkermes Investigational Site	Memphis	Tennessee	United States	38119
41	Alkermes Investigational Site	Austin	Texas	United States	78731
42	Alkermes Investigational Site	Austin	Texas	United States	78754
43	Alkermes Investigational Site	Dallas	Texas	United States	75231
44	Alkermes Investigational Site	Dallas	Texas	United States	75243
45	Alkermes Investigational Site	DeSoto	Texas	United States	75115
46	Alkermes Investigational Site	Houston	Texas	United States	77007
47	Alkermes Investigational Site	Houston	Texas	United States	77008
48	Alkermes Investigational Site	Salt Lake City	Utah	United States	84106
49	Alkermes Investigational Site	Bellevue	Washington	United States	98007
50	Alkermes Investigational Site	Richland	Washington	United States	99362
51	Alkermes Investigational Site	Burgas		Bulgaria	8000
52	Alkermes Investigational Site	Kazanlak		Bulgaria	6100
53	Alkermes Investigational Site	Lovech		Bulgaria	5500
54	Alkermes Investigational Site	Novi Iskar		Bulgaria	1280
55	Alkermes Investigational Site	Pazardzhik		Bulgaria	4400
56	Alkermes Investigational Site	Sofia		Bulgaria	1606
57	Alkermes Investigational Site	Tserova Koria		Bulgaria	8260
58	Alkermes Investigational Site	Varna		Bulgaria	9020
59	Alkermes Investigational Site	Vratsa		Bulgaria	3000
60	Alkermes Investigational Site	Brno-mesto		Czechia
61	Alkermes Investigational Site	Praha		Czechia

Sponsors and Collaborators

• Alkermes, Inc.

Investigators

• Study Director: Bernard L. Silverman, MD, Alkermes, Inc.

Study Documents (Full-Text)

• Study Protocol - Jun 13, 2014
• Statistical Analysis Plan - Dec 2, 2014

More Information

Publications

None provided.

• Responsible Party: Alkermes, Inc.
• ClinicalTrials.gov Identifier: NCT01903837
• Other Study ID Numbers: ALK3831-302
• First Posted: Jul 19, 2013
• Last Update Posted: Oct 6, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by Alkermes, Inc.: Schizophrenia; Olanzapine; Samidorphan; Alkermes
• Additional relevant MeSH terms: Schizophrenia; Naltrexone; Olanzapine; ALKS-33

Study Results

Participant Flow

Recruitment Details

This study included subjects who had a diagnosis of schizophrenia and who had not been exposed to olanzapine, clozapine, mesoridazine, chlorpromazine, or thioridazine for more than 1 week within the previous year or at any time in the 3 months prior to screening. Subjects were enrolled in study sites located in 3 countries: United States, Bulgaria, and the Czech Republic.

Pre-assignment Detail

Subjects completed a seven-day lead-in period on open-label olanzapine before being randomized into the 12-week double-blind treatment period. Baseline data includes subjects who completed the lead-in period and were randomized to a treatment group. A total of 347 subjects were enrolled in the study; 309 subjects completed the 1-week olanzapine lead-in period and were randomized to one of the 4 treatment groups in Part A

Arm/Group Title	Olz + Placebo/ Olz+Sam 20mg	Olz + Sam 5mg / Olz + Sam 5mg	Olz + Sam 10mg /Olz + Sam 10mg	Olz + Sam 20mg/ Olz + Sam 20mg
Arm/Group Description	Part A: Olanzapine (dose level determined by Investigator) + placebo tablets taken once daily Part B: Olanzapine (dose level determined by Investigator) + 20mg Samidorphan tablets taken once daily Subjects were transitioned from placebo in Part A to 20mg Samidorphan in Part B	Part A: Olanzapine (dose level determined by Investigator) + 5mg samidorphan tablets taken once daily Part B: Olanzapine (dose level determined by Investigator) + 5mg samidorphan tablets taken once daily	Part A: Olanzapine (dose level determined by Investigator) + 10mg Samidorphan tablets taken once daily Part B: Olanzapine (dose level determined by Investigator) + 10mg Samidorphan tablets taken once daily	Part A: Olanzapine (dose level determined by Investigator) + 20mg samidorphan tablets taken once daily Part B: Olanzapine (dose level determined by Investigator) + 20mg samidorphan tablets taken once daily
Period Title: Part A
STARTED	75	80	86	68
COMPLETED	56	52	58	55
NOT COMPLETED	19	28	28	13
Period Title: Part A
STARTED	54	52	57	55
COMPLETED	45	46	52	44
NOT COMPLETED	9	6	5	11

Baseline Characteristics

Arm/Group Title	Olz + Placebo	Olz + Sam 5mg	Olz + Sam 10mg	Olz + Sam 20mg	Total
Arm/Group Description	Olanzapine (dose level determined by Investigator) and placebo tablets taken once daily	Olanzapine (dose level determined by Investigator) and 5mg Samidorphan tablets taken once daily	Olanzapine (dose level determined by Investigator) and 10mg Samidorphan tablets taken once daily	Olanzapine (dose level determined by Investigator) and 20mg Samidorphan tablets taken once daily	Total of all reporting groups
Overall Participants	75	80	86	68	309
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.3 (8.14)	37.9 (8.62)	38.1 (8.00)	39.3 (8.38)	38.8 (8.30)
Sex: Female, Male (Count of Participants)
Female	22 29.3%	20 25%	21 24.4%	18 26.5%	81 26.2%
Male	53 70.7%	60 75%	65 75.6%	50 73.5%	228 73.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 5.3%	5 6.3%	5 5.8%	3 4.4%	17 5.5%
Not Hispanic or Latino	71 94.7%	75 93.8%	81 94.2%	65 95.6%	292 94.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 1.3%	0 0%	1 1.2%	2 2.9%	4 1.3%
Native Hawaiian or Other Pacific Islander	2 2.7%	0 0%	0 0%	1 1.5%	3 1%
Black or African American	44 58.7%	53 66.3%	50 58.1%	42 61.8%	189 61.2%
White	28 37.3%	26 32.5%	35 40.7%	23 33.8%	112 36.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 1.3%	0 0%	0 0%	1 0.3%
Region of Enrollment (Count of Participants)
United States	60 80%	68 85%	70 81.4%	60 88.2%	258 83.5%
Czechia	0 0%	0 0%	1 1.2%	0 0%	1 0.3%
Bulgaria	15 20%	12 15%	15 17.4%	8 11.8%	50 16.2%
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	173.4 (8.07)	173.5 (10.76)	174.8 (10.27)	174.1 (9.99)	174 (9.82)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	75.6 (12.30)	77.5 (13.07)	76.7 (13.67)	75.4 (12.81)	76.4 (12.96)
Body Mass Index (BMI) (kilograms/meters^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms/meters^2]	25.1 (3.40)	25.7 (3.18)	25.0 (3.23)	24.8 (3.41)	25.2 (3.30)
Body Mass Index (BMI) Group (Count of Participants)
Underweight (<18.5)	1 1.3%	0 0%	1 1.2%	1 1.5%	3 1%
Normal (18.5 to <25)	32 42.7%	31 38.8%	42 48.8%	32 47.1%	137 44.3%
Overweight (25 to <30)	42 56%	46 57.5%	43 50%	34 50%	165 53.4%
Obese (>=30)	0 0%	3 3.8%	0 0%	1 1.5%	4 1.3%

Outcome Measures

1. Primary Outcome

Title	Absolute Change in Total Positive and Negative Syndrome Scale (PANSS) Score
Description	Change from baseline (Day 8) to Day 92 (end of study Part A). The PANSS is a 30-item scale measuring severity of schizophrenia symptoms. Symptom severity for each item is rated on a 7-point scale (1 = absent; 7 = extreme), and the total score is added together, with a minimum score of 30 and a maximum score of 210. A higher score indicates more severe symptoms, while a lower score indicates less severe symptoms.
Time Frame	Baseline (Day 8) to Day 92 (end of study Part A)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score.

Arm/Group Title	Part A FAS 1 - Olz + Placebo	Part A FAS 1 - Olz + Sam 5mg	Part A FAS 1- Olz+ Sam 10mg	Part A FAS 1- Olz+ Sam 20mg
Arm/Group Description	Subjects who were randomized to olanzapine + placebo in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 5mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 10mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 20mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score
Measure Participants	74	75	83	68
Least Squares Mean (Standard Error) [units on a scale]	-2.9 (0.82)	-1.5 (0.85)	-2.7 (0.79)	-2.5 (0.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A FAS 1 - Olz + Placebo, Part A FAS 1 - Olz + Sam 5mg, Part A FAS 1- Olz+ Sam 10mg, Part A FAS 1- Olz+ Sam 20mg
	Comments
	Type of Statistical Test	Equivalence
	Comments	Equivalence margin of 10 points
Statistical Test of Hypothesis	p-Value	0.3
	Comments
	Method	Least Square Mean Difference
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -2.0 to 2.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.17
	Estimation Comments

2. Secondary Outcome

Title	Percent Change in Body Weight (Kilogram) From Baseline to Day 92
Description	Percent change from baseline (Day 8) to the end of Part A (Day 92)
Time Frame	Baseline (Day 8) to Day 92 (end of study Part A)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score. FAS 2 efficacy analysis population included all FAS 1 subjects who gained weight during the 1-week OLZ lead-in period prior to randomization and had at least one postbaseline weight assessment.

Arm/Group Title	Part A FAS 1 - Olz + Placebo	Part A FAS 1 - Olz + Sam 5mg	Part A FAS 1- Olz + Sam 10mg	Part A FAS 1- Olz + Sam 20mg	Part A FAS 2- Olz + Placebo	Part A FAS 2- Olz + Sam 5mg	Part A FAS 2- Olz + Sam 10mg	Part A FAS 2- Olz + 20mg
Arm/Group Description	Subjects who were randomized to olanzapine + placebo in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 5mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 10mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 20mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	All FAS 1 subjects who were randomized to olanzapine + placebo in study Part A, gained weight during the first week of olanzapine treatment prior to randomization, and had at least one post-baseline weight assessment.	All FAS 1 subjects who were randomized to olanzapine + samidorphan 5mg in study Part A, gained weight during the first week of olanzapine treatment prior to randomization, and had at least one post-baseline weight assessment.	All FAS 1 subjects who were randomized to olanzapine + samidorphan 10mg in study Part A, gained weight during the first week of olanzapine treatment prior to randomization, and had at least one post-baseline weight assessment.	All FAS 1 subjects who were randomized to olanzapine + samidorphan 20mg in study Part A, gained weight during the first week of olanzapine treatment prior to randomization, and had at least one post-baseline weight assessment.
Measure Participants	74	75	83	67	45	50	53	46
Least Squares Mean (95% Confidence Interval) [percent change]	4.1	2.8	2.1	2.9	5.3	3.8	2.2	1.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A FAS 1 - Olz + Placebo, Part A FAS 1 - Olz + Sam 5mg, Part A FAS 1- Olz+ Sam 10mg, Part A FAS 1- Olz+ Sam 20mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A FAS 2- Olz + Placebo, Part A FAS 2- Olz + Sam 5mg, Part A FAS 2- Olz + Sam 10mg, Part A FAS 2- Olz + 20mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Absolute Change in Body Weight (kg) From Baseline to Day 92
Description	Change from randomization (Day 8) to the end of Part A (Week 12; Day 92)
Time Frame	Baseline (Day 8) to Day 92 (end of study Part A)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score. FAS 2 efficacy analysis population included all FAS 1 subjects who gained weight during the 1-week OLZ lead-in period prior to randomization and had at least one postbaseline weight assessment.

Arm/Group Title	Part A FAS 1- Olz + Placebo	Part A FAS 1- Olz + Sam 5mg	Part A FAS 1- Olz + Sam 10mg	Part A FAS 1- Olz + Sam 20mg	Part A FAS 2- Olz + Placebo	Part A FAS 2- Olz + Sam 5mg	Part A FAS 2- Olz + Sam 10mg	Part A FAS 2- Olz + Sam 20mg
Arm/Group Description	Subjects who were randomized to olanzapine + placebo in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + 5mg samidorphan in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + 10mg samidorphan in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + 20mg samidorphan in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	All FAS 1 subjects who were randomized to olanzapine + placebo in study Part A, gained weight during the first week of olanzapine treatment prior to randomization, and had at least one post-baseline weight assessment.	All FAS 1 subjects who were randomized to olanzapine + samidorphan 5mg in study Part A, gained weight during the first week of olanzapine treatment prior to randomization, and had at least one post-baseline weight assessment.	All FAS 1 subjects who were randomized to olanzapine + samidorphan 10mg in study Part A, gained weight during the first week of olanzapine treatment prior to randomization, and had at least one post-baseline weight assessment.	All FAS 1 subjects who were randomized to olanzapine + samidorphan 20mg in study Part A, gained weight during the first week of olanzapine treatment prior to randomization, and had at least one post-baseline weight assessment.
Measure Participants	74	75	83	67	45	50	53	47
Least Squares Mean (95% Confidence Interval) [kg]	2.9	2.1	1.5	2.2	3.8	2.9	1.5	1.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A FAS 1 - Olz + Placebo, Part A FAS 1 - Olz + Sam 5mg, Part A FAS 1- Olz+ Sam 10mg, Part A FAS 1- Olz+ Sam 20mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A FAS 2- Olz + Placebo, Part A FAS 2- Olz + Sam 5mg, Part A FAS 2- Olz + Sam 10mg, Part A FAS 2- Olz + 20mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Percentage of Subjects Exhibiting Significant Weight Gain at Day 92
Description	Significant weight gain will include a >=5%, >= 7%, or >=10% gain in body weight from baseline (Day 8) to Day 92 (end of study Part A)
Time Frame	Baseline (Day 8) to Day 92 (end of study Part A)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score. FAS 2 efficacy analysis population included all FAS 1 subjects who gained weight during the 1-week OLZ lead-in period prior to randomization and had at least one postbaseline weight assessment.

Arm/Group Title	Part A FAS 1- Olz + Placebo	Part A FAS 1- Olz + Sam 5mg	Part A FAS 1- Olz + Sam 10mg	Part A FAS 1- Olz + Sam 20mg	Part A FAS 2- Olz + Placebo	Part A FAS 2- Olz + Sam 5mg	Part A FAS 2- Olz + Sam 10mg	Part A FAS 2- Olz + Sam 20mg
Arm/Group Description	Subjects who were randomized to olanzapine + placebo in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 5mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 10mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 20mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	All FAS 1 subjects who were randomized to olanzapine + placebo in study Part A, gained weight during the first week of olanzapine treatment prior to randomization and had at least one post-baseline weight assessment.	All FAS 1 subjects who were randomized to olanzapine + samidorphan 5mg in study Part A, gained weight during the first week of olanzapine treatment prior to randomization and had at least one post-baseline weight assessment.	Subjects who were randomized to olanzapine + samidorphan 10mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 20mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score
Measure Participants	56	52	59	54	35	35	36	35
>= 5% weight gain	20 26.7%	18 22.5%	16 18.6%	16 23.5%	14 4.5%	13 NaN	8 NaN	8 NaN
>= 7% weight gain	14 18.7%	8 10%	9 10.5%	12 17.6%	11 3.6%	7 NaN	4 NaN	7 NaN
>=10% weight gain	10 13.3%	3 3.8%	4 4.7%	5 7.4%	8 2.6%	3 NaN	3 NaN	1 NaN

5. Secondary Outcome

Title	Change in Clinical Global Impressions - Severity (CGI-S) From Baseline to Day 92
Description	Change in CGI-S score from baseline (Day 8) to the end of Part A (Week 12; Day 92). The CGI-S is a 7-point scale intended to measure the severity of a patient's illness at the time of assessment. Scores range from 1 (normal) to 7(extremely ill), so a higher score is correlative to more severe illness.
Time Frame	Baseline (Day 8) to Day 92 (end of study Part A)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score.

Arm/Group Title	Part A FAS 1 - OLZ + Placebo	Part A FAS 1 - Olz + Sam 5mg	Part A FAS 1- Olz + Sam 10mg	Part A FAS 1- Olz + Sam 20mg
Arm/Group Description	Subjects who were randomized to olanzapine + placebo in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 5mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 10mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score	Subjects who were randomized to olanzapine + samidorphan 20mg in study Part A, received at least one dose of study drug, and had at least one post-baseline assessment of PANSS total score
Measure Participants	74	75	83	68
Least Squares Mean (Standard Error) [units on a scale]	-0.0 (0.05)	-0.1 (0.05)	-0.0 (0.05)	-0.1 (0.05)

Adverse Events

Time Frame	Safety assessments are presented for all dosing groups in both Study Parts A and B, i.e. 24 weeks
Arm/Group Title	Part A- Olz + Placebo		Part A-Olz + Sam 5mg		Part A- Olz + Sam 10mg		Part A- Olz + Sam 20mg		Part B-Olz +Placebo/ Olz+Sam 20mg		Part B- Olz + Sam 5mg / Olz +Sam 5mg		Part B- Olz + Sam 10mg/ Olz + Sam 10mg		Part B-Olz + Sam 20mg/ Olz + Sam 20mg
Arm/Group Description	Olanzapine (dose level determined by Investigator) + placebo tablets taken once daily		Olanzapine (dose level determined by Investigator) + 5mg samidorphan tablets taken once daily		Olanzapine (dose level determined by Investigator) + 10mg Samidorphan tablets taken once daily		Olanzapine (dose level determined by Investigator) + 20mg samidorphan tablets taken once daily		Olanzapine (dose level determined by Investigator) + 20mg Samidorphan tablets taken once daily Subjects were transitioned from placebo in Part A to 20mg Samidorphan in Part B		Olanzapine (dose level determined by Investigator) + 5mg samidorphan tablets taken once daily		Olanzapine (dose level determined by Investigator) + 10mg Samidorphan tablets taken once daily		Olanzapine (dose level determined by Investigator) + 20mg samidorphan tablets taken once daily
All Cause Mortality
	Part A- Olz + Placebo		Part A-Olz + Sam 5mg		Part A- Olz + Sam 10mg		Part A- Olz + Sam 20mg		Part B-Olz +Placebo/ Olz+Sam 20mg		Part B- Olz + Sam 5mg / Olz +Sam 5mg		Part B- Olz + Sam 10mg/ Olz + Sam 10mg		Part B-Olz + Sam 20mg/ Olz + Sam 20mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/80 (0%)		0/86 (0%)		0/68 (0%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Serious Adverse Events
	Part A- Olz + Placebo		Part A-Olz + Sam 5mg		Part A- Olz + Sam 10mg		Part A- Olz + Sam 20mg		Part B-Olz +Placebo/ Olz+Sam 20mg		Part B- Olz + Sam 5mg / Olz +Sam 5mg		Part B- Olz + Sam 10mg/ Olz + Sam 10mg		Part B-Olz + Sam 20mg/ Olz + Sam 20mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/75 (2.7%)		3/80 (3.8%)		4/86 (4.7%)		4/68 (5.9%)		1/54 (1.9%)		1/52 (1.9%)		1/57 (1.8%)		0/55 (0%)
Infections and infestations
Subcutaneous abscess	0/75 (0%)		0/80 (0%)		0/86 (0%)		0/68 (0%)		0/54 (0%)		1/52 (1.9%)		0/57 (0%)		0/55 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/75 (0%)		0/80 (0%)		1/86 (1.2%)		0/68 (0%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Nervous system disorders
Ischaemic stroke	1/75 (1.3%)		0/80 (0%)		0/86 (0%)		0/68 (0%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Psychiatric disorders
Schizophrenia	1/75 (1.3%)		2/80 (2.5%)		1/86 (1.2%)		3/68 (4.4%)		1/54 (1.9%)		0/52 (0%)		1/57 (1.8%)		0/55 (0%)
Suicidal ideation	0/75 (0%)		1/80 (1.3%)		0/86 (0%)		1/68 (1.5%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Agitation	0/75 (0%)		0/80 (0%)		1/86 (1.2%)		0/68 (0%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Anxiety	0/75 (0%)		0/80 (0%)		1/86 (1.2%)		0/68 (0%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Other (Not Including Serious) Adverse Events
	Part A- Olz + Placebo		Part A-Olz + Sam 5mg		Part A- Olz + Sam 10mg		Part A- Olz + Sam 20mg		Part B-Olz +Placebo/ Olz+Sam 20mg		Part B- Olz + Sam 5mg / Olz +Sam 5mg		Part B- Olz + Sam 10mg/ Olz + Sam 10mg		Part B-Olz + Sam 20mg/ Olz + Sam 20mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/75 (44%)		25/80 (31.3%)		33/86 (38.4%)		33/68 (48.5%)		11/54 (20.4%)		10/52 (19.2%)		11/57 (19.3%)		12/55 (21.8%)
Gastrointestinal disorders
Nausea	4/75 (5.3%)		5/80 (6.3%)		4/86 (4.7%)		5/68 (7.4%)		6/54 (11.1%)		1/52 (1.9%)		0/57 (0%)		0/55 (0%)
Dry mouth	4/75 (5.3%)		2/80 (2.5%)		5/86 (5.8%)		6/68 (8.8%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Constipation	1/75 (1.3%)		0/80 (0%)		5/86 (5.8%)		2/68 (2.9%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Vomiting	0/75 (0%)		0/80 (0%)		0/86 (0%)		0/68 (0%)		6/54 (11.1%)		0/52 (0%)		1/57 (1.8%)		0/55 (0%)
Toothache	4/75 (5.3%)		0/80 (0%)		0/86 (0%)		2/68 (2.9%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Infections and infestations
Nasopharyngitis	0/75 (0%)		0/80 (0%)		0/86 (0%)		0/68 (0%)		0/54 (0%)		3/52 (5.8%)		4/57 (7%)		2/55 (3.6%)
Investigations
Weight increased	9/75 (12%)		8/80 (10%)		9/86 (10.5%)		6/68 (8.8%)		3/54 (5.6%)		6/52 (11.5%)		2/57 (3.5%)		3/55 (5.5%)
Weight decreased	0/75 (0%)		0/80 (0%)		0/86 (0%)		0/68 (0%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		3/55 (5.5%)
Metabolism and nutrition disorders
Increased appetite	6/75 (8%)		5/80 (6.3%)		5/86 (5.8%)		6/68 (8.8%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Nervous system disorders
Somnolence	3/75 (4%)		10/80 (12.5%)		11/86 (12.8%)		8/68 (11.8%)		2/54 (3.7%)		0/52 (0%)		3/57 (5.3%)		4/55 (7.3%)
Sedation	3/75 (4%)		0/80 (0%)		4/86 (4.7%)		8/68 (11.8%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Dizziness	1/75 (1.3%)		0/80 (0%)		3/86 (3.5%)		6/68 (8.8%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Headache	4/75 (5.3%)		3/80 (3.8%)		1/86 (1.2%)		1/68 (1.5%)		1/54 (1.9%)		0/52 (0%)		4/57 (7%)		1/55 (1.8%)
Tremor	4/75 (5.3%)		0/80 (0%)		0/86 (0%)		0/68 (0%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)
Psychiatric disorders
Insomnia	4/75 (5.3%)		2/80 (2.5%)		2/86 (2.3%)		1/68 (1.5%)		0/54 (0%)		0/52 (0%)		0/57 (0%)		0/55 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Should an Investigator desire to disclose study results, Sponsor will review the results disclosure prior to public release and can embargo the disclosure for a period of at least 60 days. Revisions to the disclosure will be negotiated in good faith. For a multicenter study the Investigators agree to publish/publicly present the results together with the other sites for the 12 month period after study results are available unless Sponsor grants written permission in advance.