DayBreak: Effect of Lu AF35700 in Patients With Treatment-resistant Schizophrenia

• Sponsor: H. Lundbeck A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02717195
• Collaborator: (none)
• Enrollment: 1,098
• Locations: 147
• Arms: 4
• Duration (Months): 30.2
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To evaluate the efficacy of 10 and 20 mg/day of Lu AF35700 on schizophrenia symptoms in patients with treatment-resistant schizophrenia (TRS)

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Risperidone; Drug: Olanzapine; Drug: Lu AF35700; Drug: Lu AF35700	Phase 3

Detailed Description

The study consists of a Screening Period (3 weeks), a single-blind Prospective Confirmation (PC) Period (6 weeks), a Double-blind Treatment (DBT) Period (10 weeks), and a Safety Follow-up Period (6 weeks).

Patients who did not fulfil the randomization criteria for the DBT Period, were withdrawn from the study after the PC period.

Patients who fulfilled the randomization criteria for the DBT Period, continued into the DBT Period and were randomized into one of 3 treatment arms (1:1:1) with either Lu AF35700 10 mg/day, Lu AF35700 20 mg/day or to continue the treatment allocated in PC Period (olanzapine or risperidone) at the dose set at last visit of PC Period. This mean that approximately one third of the confirmed treatment-resistant patients were randomised back to the failed treatment used in the PC Period.

Data was not collected separately for the DBT Olanzapine and DBT Risperidone participants, and there was no intent to compare Lu AF35700 to each drug separately.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1098 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Interventional, Randomised, Double-blind, Active-controlled, Fixed-dose Study of Lu AF35700 in Patients With Treatment-resistant Schizophrenia
• Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Aug 30, 2018
• Actual Study Completion Date: Oct 8, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prospective Confirmation (PC) Period Single (patient)-blinded treatment period with risperidone or olanzapine for 6 weeks	Drug: Risperidone; 4-6 mg/day, encapsulated tablets, orally; Drug: Olanzapine; 15-20 mg/day, encapsulated tablets, orally
Experimental: Double-blind Treatment (DBT) Period, Lu AF35700 10 mg Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks	Drug: Lu AF35700; 10 mg/day, encapsulated tablets, orally
Experimental: DBT Period, Lu AF35700 20 mg Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks	Drug: Lu AF35700; 20 mg/day, encapsulated tablets, orally
Experimental: DBT Period, Continued treatment from PC Period Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period	Drug: Risperidone; 4-6 mg/day, encapsulated tablets, orally; Drug: Olanzapine; 15-20 mg/day, encapsulated tablets, orally

Outcome Measures

Primary Outcome Measures

1. Change From Randomization to Week 10 in Positive and Negative Syndrome Scale (PANSS) Total Score [From Randomization to Week 10]

   PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia.

Secondary Outcome Measures

1. Change From Randomization to Week 10 in PSP Total Personal and Social Performance (PSP) Total Score [From Randomization to Week 10]

   PSP is a clinician-rated scale designed and validated to measure a patient's current level of social functioning. It consists of 4 items: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviours. Each items were assessed on a 6-point scale, from 1 (absent) to 6 (very severe). PSP score was calculated as sum of all the items on the scale and ranged from 4 to 100. A higher score represents more severe functional impairment.

2. Change From Randomization to Week 10 in Global Clinical Impression - Severity of Illness (CGI-S) Score [From Randomization to Week 10]

   CGI-S provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). Higher scores indicate worsening.

3. Response at Week 10, Defined as ≥20% Reduction in PANSS Total Score, PANSS (Positive and Negative Syndrome Scale) Total Score ≤70, CGI-S (Clinical Global Impression Scale - Severity of Illness) Score <4 [From Randomization to Week 10]

   PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement. The Clinical Global Impression scale - severity of illness (CGI-S) is administered by the investigator. The patient is rated on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). A reduction in scale indicates improvement.

4. Response at Week 10, Defined as ≥20% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization [From Randomization to Week 10]

   PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.

5. Response at Week 10, Defined as ≥30% Reduction in PANSS Total Score From Randomization [From Randomization to Week 10]

   Positive and Negative Syndrome Scale (PANSS) total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.

6. Response at Week 10, Defined as ≥40% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization [From Randomization to Week 10]

   PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.

7. Response at Week 10, Defined as ≥50% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization [From Randomization to Week 10]

   PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• The patient has schizophrenia, diagnosed according to DSM-5(TM) (Diagnostic and Statistical Manual of Mental Disorders) and confirmed by the Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders

• The patient is either an inpatient at a psychiatric setting or outpatient consulting a psychiatrist.

• Patients should be treated with adequate dose(s) and agent(s) of antipsychotic treatment for at least 2 weeks prior to Screening

• The patient has failed to show an adequate response in the level of psychotic symptoms despite at least one documented treatment trial with an adequate dose of an antipsychotic agent prescribed for an adequate time (at least lasting for 6 weeks) during 2 years prior to Screening. The failure to respond to the current antipsychotic treatment trial may be considered a retrospective failed treatment, if the patient was treated for 6 weeks with adequate dose(s) and agent(s)

• The patient has a PANSS total score of ≥80 and a score of ≥4 on at least 2 of the following PANSS items (at Screening and at the first visit of Period A)

• The patient has a CGI-S score of ≥4 at Screening and at the first visit of Period A

Exclusion Criteria:

• The patient has any current primary psychiatric disorder other than schizophrenia as assessed by the Mini International Neuropsychiatric Interview (MINI)

• The patient is experiencing an acute exacerbation of his/her psychotic symptoms

• The patient has not responded to treatment with clozapine

Other protocol defined inclusion and exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	US1018	Bellflower	California	United States	90706
2	US1041	Cerritos	California	United States	90703
3	US1062	Costa Mesa	California	United States	92626
4	US1463	Culver City	California	United States	90230
5	US1104	Garden Grove	California	United States	92845
6	US1118	Glendale	California	United States	91206
7	US1114	National City	California	United States	91950
8	US1452	Oceanside	California	United States	92056-4509
9	US1459	Oceanside	California	United States	92056-4515
10	US1399	Orange	California	United States	91945
11	US1368	Orange	California	United States	92868
12	US1391	San Bernardino	California	United States	92408-3332
13	US1464	Santa Ana	California	United States	92705-3610
14	US1384	Sherman Oaks	California	United States	91403-1747
15	US1392	Torrance	California	United States	90502-4432
16	US1396	Washington	District of Columbia	United States	20016
17	US1395	Bradenton	Florida	United States	32751
18	US1253	Jacksonville	Florida	United States	32256
19	US1130	Miami	Florida	United States	33122
20	US1318	North Miami	Florida	United States	33161
21	US1129	North Miami	Florida	United States	33162
22	US1402	Oakland Park	Florida	United States	33334-4400
23	US1229	Orange City	Florida	United States	32763
24	US1453	Tampa	Florida	United States	33609-2231
25	US1403	Atlanta	Georgia	United States	30328
26	US1009	Atlanta	Georgia	United States	30331
27	US1442	Decatur	Georgia	United States	30030
28	US1046	Chicago	Illinois	United States	60640
29	US1423	Hoffman Estates	Illinois	United States	60169-1067
30	US1398	Shreveport	Louisiana	United States	71101-4603
31	US1404	Shreveport	Louisiana	United States	71104-2136
32	US1086	Flowood	Mississippi	United States	39232
33	US1444	Las Vegas	Nevada	United States	89102-1943
34	US1426	Berlin	New Jersey	United States	08009
35	US1454	Marlton	New Jersey	United States	08053
36	US1405	Glen Oaks	New York	United States	11004
37	US1244	Jamaica	New York	United States	11432
38	US1394	New York	New York	United States	10032
39	US1416	New York	New York	United States	10035-6000
40	US1171	Rochester	New York	United States	14618
41	US1190	Staten Island	New York	United States	10312
42	US1390	Charlotte	North Carolina	United States	28204-3110
43	US1401	Charlotte	North Carolina	United States	28211-1064
44	US1441	Hickory	North Carolina	United States	28601-5045
45	US1124	Norristown	Pennsylvania	United States	19403
46	US1319	Charleston	South Carolina	United States	29407
47	US1451	Austin	Texas	United States	78754-5122
48	US1065	Dallas	Texas	United States	75243
49	US1443	Fort Worth	Texas	United States	76104
50	BG1030	Burgas		Bulgaria
51	BG1028	Kazanlak		Bulgaria
52	BG1003	Lovech		Bulgaria
53	BG1032	Pazardzhik		Bulgaria
54	BG1008	Plovdiv		Bulgaria
55	BG1024	Sofia		Bulgaria
56	BG1026	Sofia		Bulgaria
57	BG1022	Tserova Koria		Bulgaria
58	BG1033	Varna		Bulgaria
59	BG1034	Varna		Bulgaria
60	BG1029	Veliko Tŭrnovo		Bulgaria
61	BG1027	Vratsa		Bulgaria
62	CA1017	Chatham		Canada
63	CA1034	Kingston		Canada
64	CA1003	Montréal		Canada
65	CA1033	Montréal		Canada
66	CA1029	Penticton		Canada
67	CA1039	Québec		Canada
68	CZ1023	Brno		Czechia
69	CZ1032	Brno		Czechia
70	CZ1037	Hostivice		Czechia
71	CZ1013	Lnare		Czechia
72	CZ1038	Praha		Czechia
73	EE1016	Pärnu		Estonia
74	EE1007	Tallinn		Estonia
75	EE1017	Viljandi		Estonia
76	FI1032	Espoo		Finland
77	FI1030	Kuopio		Finland
78	FI1027	Turku		Finland
79	MX1024	Durango		Mexico
80	MX1011	Guadalajara		Mexico
81	MX1021	Guadalajara		Mexico
82	MX1022	Guadalajara		Mexico
83	MX1020	Mexico		Mexico
84	MX1005	Monterrey		Mexico
85	MX1007	Monterrey		Mexico
86	MX1015	Monterrey		Mexico
87	MX1016	Monterrey		Mexico
88	MX1018	San Luis Potosi		Mexico
89	PL1025	Bełchatów		Poland
90	PL1043	Bialystok		Poland
91	PL1026	Gorlice		Poland
92	PL1060	Lodz		Poland
93	PL1027	Lublin		Poland
94	PL1058	Pruszcz Gdanski		Poland
95	PL1061	Pruszkow		Poland
96	PL1059	Torun		Poland
97	PL1051	Wroclaw		Poland
98	RO1024	Bucuresti		Romania
99	RO1022	Câmpulung		Romania
100	RO1025	Sibiu		Romania
101	RO1004	Târgu-Mureş		Romania
102	RU1021	Nikol'skoye	Gatchinckiy District	Russian Federation
103	RU1009	Arkhangelsk		Russian Federation
104	RU1006	Moscow		Russian Federation
105	RU1051	Moscow		Russian Federation
106	RU1055	Moscow		Russian Federation
107	RU1023	Saint Petersburg		Russian Federation
108	RU1028	Saint Petersburg		Russian Federation
109	RU1030	Saint Petersburg		Russian Federation
110	RU1031	Saint Petersburg		Russian Federation
111	RU1052	Saint Petersburg		Russian Federation
112	RU1053	Saint Petersburg		Russian Federation
113	RU1056	Saint Petersburg		Russian Federation
114	RU1049	St. Petersburg		Russian Federation
115	RU1050	Yaroslavl		Russian Federation
116	RS1008	Belgrade		Serbia
117	RS1010	Belgrade		Serbia
118	RS1012	Belgrade		Serbia
119	RS1011	Kragujevac		Serbia
120	RS1016	Kragujevac		Serbia
121	RS1017	Kragujevac		Serbia
122	RS1003	Nis		Serbia
123	RS1009	Novi Knezevac		Serbia
124	SK1014	Bratislava		Slovakia
125	SK1024	Bratislava		Slovakia
126	SK1015	Roznava		Slovakia
127	SK1025	Svidnik		Slovakia
128	SK1026	Zlate Moravce		Slovakia
129	ES1047	Barcelona		Spain
130	ES1012	Madrid		Spain
131	ES1008	Malaga		Spain
132	ES1048	Oviedo		Spain
133	ES1049	Zamora		Spain
134	UA1019	Dnipropetrovsk		Ukraine
135	UA1017	Kharkiv		Ukraine
136	UA1022	Kharkiv		Ukraine
137	UA1031	Kharkiv		Ukraine
138	UA1035	Kharkiv		Ukraine
139	UA1028	Kherson		Ukraine
140	UA1029	Kherson		Ukraine
141	UA1027	Kiev		Ukraine
142	UA1030	Kiev		Ukraine
143	UA1033	Lviv		Ukraine
144	UA1020	Odessa		Ukraine
145	UA1032	Odessa		Ukraine
146	UA1001	Poltava		Ukraine
147	UA1036	Vinnitsa		Ukraine

Sponsors and Collaborators

• H. Lundbeck A/S

Investigators

• Study Director: Email contact via H. Lundbeck A/S, [e-mail]

Study Documents (Full-Text)

• Study Protocol - Jun 27, 2017
• Statistical Analysis Plan - Oct 18, 2018

More Information

Publications

None provided.

• Responsible Party: H. Lundbeck A/S
• ClinicalTrials.gov Identifier: NCT02717195
• Other Study ID Numbers: 16159A; 2014-003569-12
• First Posted: Mar 23, 2016
• Last Update Posted: Nov 25, 2019
• Last Verified: Oct 1, 2019

• Additional relevant MeSH terms: Schizophrenia; Olanzapine; Risperidone

Study Results

Participant Flow

Pre-assignment Detail	Patients who did not fulfil the randomization criteria for the DBT Period, were withdrawn from the study after the PC period. Patients who fulfilled the randomization criteria for the DBT Period, continued into the DBT Period. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment.

Arm/Group Title	Prospective Confirmation (PC) Period, Risperidone	PC Period, Olanzapine	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Single (patient)-blinded treatment period with risperidone or olanzapine for 6 weeks Risperidone: 4-6 mg/day, encapsulated tablets, orally	Single (patient)-blinded treatment period with risperidone or olanzapine for 6 weeks Olanzapine: 15-20 mg/day, encapsulated tablets, orally	Lu AF35700: 10 mg/day, encapsulated tablets, orally for 10 weeks	Lu AF35700: 20 mg/day, encapsulated tablets, orally for 10 weeks	Patients in this arm will continue the treatment allocated in the PC Period at the dose set at last visit of the PC Period. The analysis is made independent on which treatment the patient was on (risperidone or olanzapine)
Period Title: Prospective Confirmation (PC) Period
STARTED	711	387	0	0	0
COMPLETED	421	276	0	0	0
NOT COMPLETED	290	111	0	0	0
Period Title: Prospective Confirmation (PC) Period
STARTED	0	0	235	232	230
COMPLETED	0	0	198	188	200
NOT COMPLETED	0	0	37	44	30

Baseline Characteristics

Arm/Group Title	Non-randomized Patients	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period	Total
Arm/Group Description	Patients not randomized into the double-blind treatment period, i.e. withdrawn from the study during or after the PC period, were analyzed as one arm independent of treatment.	Lu AF35700: 10 mg/day, encapsulated tablets, orally for 10 weeks	Lu AF35700: 20 mg/day, encapsulated tablets, orally for 10 weeks	Patients in this arm continued with the same treatment and dose as at the last visit of the PC Period. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment.	Total of all reporting groups
Overall Participants	401	235	232	230	1098
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44 (11.05)	42.6 (12.14)	42.3 (11.44)	43.2 (11.19)	43 (11.41)
Sex: Female, Male (Count of Participants)
Female	147 36.7%	91 38.7%	94 40.5%	89 38.7%	421 38.3%
Male	254 63.3%	144 61.3%	138 59.5%	141 61.3%	677 61.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	35 8.7%	6 2.6%	10 4.3%	8 3.5%	59 5.4%
Not Hispanic or Latino	224 55.9%	46 19.6%	42 18.1%	45 19.6%	357 32.5%
Unknown or Not Reported	142 35.4%	183 77.9%	180 77.6%	177 77%	682 62.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.2%	0 0%	1 0.4%	0 0%	2 0.2%
Asian	4 1%	1 0.4%	0 0%	1 0.4%	6 0.5%
Native Hawaiian or Other Pacific Islander	2 0.5%	0 0%	0 0%	0 0%	2 0.2%
Black or African American	172 42.9%	36 15.3%	33 14.2%	34 14.8%	275 25%
White	186 46.4%	176 74.9%	179 77.2%	178 77.4%	719 65.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	36 9%	22 9.4%	19 8.2%	17 7.4%	94 8.6%
PANSS total score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	97.25 (11.21)	96.96 (9.17)	98.23 (9.29)	98.40 (9.84)	97.6 (10.12)
CGI-S score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.82 (0.60)	4.88 (0.59)	5.00 (0.57)	4.90 (0.53)	4.89 (0.58)

Outcome Measures

1. Primary Outcome

Title	Change From Randomization to Week 10 in Positive and Negative Syndrome Scale (PANSS) Total Score
Description	PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia.
Time Frame	From Randomization to Week 10

Outcome Measure Data

Analysis Population Description

Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.

Arm/Group Title	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Lu AF35700: 10 mg/day, encapsulated tablets, orally for 10 weeks	Lu AF35700: 20 mg/day, encapsulated tablets, orally for 10 weeks	Patients in this arm will continue with the same treatment and dose as at the last visit of the PC Period (olanzapine or risperidone)
Measure Participants	201	189	202
Mean (Standard Error) [units on a scale]	-10.01 (0.96)	-8.22 (0.98)	-9.90 (0.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg, DBT Period, Continued Treatment From PC Period
	Comments	The mean changes from Randomization in PANSS total score was analysed using a MMRM approach. The model included the fixed, categorical effects of treatment, country, week, treatment-by-week interaction, PC Period treatment, PC Period treatment-by-week interaction, and the continuous covariates of Randomization score and Randomization score-by-week interaction with an unstructured covariance structure to model the within-patient errors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9196
	Comments	Multiplicity adjustment was planned for the testing of the primary enpoint, but was not applied since all p-values>0.05.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -2.37 to 2.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DBT Period, Lu AF35700 20 mg, DBT Period, Continued Treatment From PC Period
	Comments	The mean changes from Randomization in PANSS total score was analysed using a MMRM approach. The model included the fixed, categorical effects of treatment, country, week, treatment-by-week interaction, PC Period treatment, PC Period treatment-by-week interaction, and the continuous covariates of Randomization score and Randomization score-by-week interaction with an unstructured covariance structure to model the within-patient errors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1474
	Comments	Multiplicity adjustment was planned for the testing of the primary endpoint, but was not applied since all p-values>0.05.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.67
	Confidence Interval	(2-Sided) 95%; -0.59 to 3.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Randomization to Week 10 in PSP Total Personal and Social Performance (PSP) Total Score
Description	PSP is a clinician-rated scale designed and validated to measure a patient's current level of social functioning. It consists of 4 items: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviours. Each items were assessed on a 6-point scale, from 1 (absent) to 6 (very severe). PSP score was calculated as sum of all the items on the scale and ranged from 4 to 100. A higher score represents more severe functional impairment.
Time Frame	From Randomization to Week 10

Outcome Measure Data

Analysis Population Description

Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.

Arm/Group Title	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 10 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 20 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period Risperidone: 4-6 mg/day, encapsulated tablets, orally Olanzapine: 15-20 mg/day, encapsulated tablets, orally
Measure Participants	204	197	203
Mean (Standard Error) [units on a scale]	4.90 (0.96)	3.23 (0.98)	3.94 (0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg, DBT Period, Continued Treatment From PC Period
	Comments	The mean changes from Randomization in PSP score was analysed using a MMRM approach. The model included the fixed, categorical effects of treatment, country, week, treatment-by-week interaction, PC Period treatment, PC Period treatment-by-week interaction, and the continuous covariates of Randomization score and Randomization score-by-week interaction with an unstructured covariance structure to model the within-patient errors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2998
	Comments	Multiplicity adjustment was planned for the testing of the primary endpoint, but was not applied since all p-values>0.05.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; -0.86 to 2.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DBT Period, Lu AF35700 20 mg, DBT Period, Continued Treatment From PC Period
	Comments	The mean changes in PSP score was analysed using a MMRM approach. The model included the fixed, categorical effects of treatment, country, week, treatment-by-week interaction, PC Period treatment, PC Period treatment-by-week interaction, and the continuous covariates of Randomization score and Randomization score-by-week interaction with an unstructured covariance structure to model the within-patient errors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4478
	Comments	Multiplicity adjustment was planned for the testing of the primary endpoint, but was not applied since all p-values>0.05.
	Method	Mixed model repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) 95%; -2.54 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Randomization to Week 10 in Global Clinical Impression - Severity of Illness (CGI-S) Score
Description	CGI-S provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). Higher scores indicate worsening.
Time Frame	From Randomization to Week 10

Outcome Measure Data

Analysis Population Description

Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.

Arm/Group Title	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 10 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 20 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period Risperidone: 4-6 mg/day, encapsulated tablets, orally Olanzapine: 15-20 mg/day, encapsulated tablets, orally
Measure Participants	232	231	228
Mean (Standard Error) [units on a scale]	-0.59 (0.06)	-0.54 (0.06)	-0.57 (0.06)

4. Secondary Outcome

Title	Response at Week 10, Defined as ≥20% Reduction in PANSS Total Score, PANSS (Positive and Negative Syndrome Scale) Total Score ≤70, CGI-S (Clinical Global Impression Scale - Severity of Illness) Score <4
Description	PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement. The Clinical Global Impression scale - severity of illness (CGI-S) is administered by the investigator. The patient is rated on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). A reduction in scale indicates improvement.
Time Frame	From Randomization to Week 10

Outcome Measure Data

Analysis Population Description

Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.

Arm/Group Title	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 10 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 20 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period Risperidone: 4-6 mg/day, encapsulated tablets, orally Olanzapine: 15-20 mg/day, encapsulated tablets, orally
Measure Participants	201	189	202
Count of Participants [Participants]	21 5.2%	18 7.7%	12 5.2%

5. Secondary Outcome

Title	Response at Week 10, Defined as ≥20% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization
Description	PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.
Time Frame	From Randomization to Week 10

Outcome Measure Data

Analysis Population Description

Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.

Arm/Group Title	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 10 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 20 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period Risperidone: 4-6 mg/day, encapsulated tablets, orally Olanzapine: 15-20 mg/day, encapsulated tablets, orally
Measure Participants	201	189	202
Count of Participants [Participants]	82 20.4%	59 25.1%	77 33.2%

6. Secondary Outcome

Title	Response at Week 10, Defined as ≥30% Reduction in PANSS Total Score From Randomization
Description	Positive and Negative Syndrome Scale (PANSS) total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.
Time Frame	From Randomization to Week 10

Outcome Measure Data

Analysis Population Description

Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.

Arm/Group Title	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 10 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 20 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period Risperidone: 4-6 mg/day, encapsulated tablets, orally Olanzapine: 15-20 mg/day, encapsulated tablets, orally
Measure Participants	201	189	202
Count of Participants [Participants]	42 10.5%	30 12.8%	45 19.4%

7. Secondary Outcome

Title	Response at Week 10, Defined as ≥40% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization
Description	PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.
Time Frame	From Randomization to Week 10

Outcome Measure Data

Analysis Population Description

Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.

Arm/Group Title	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 10 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 20 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period Risperidone: 4-6 mg/day, encapsulated tablets, orally Olanzapine: 15-20 mg/day, encapsulated tablets, orally
Measure Participants	201	189	202
Count of Participants [Participants]	23 5.7%	15 6.4%	16 6.9%

8. Secondary Outcome

Title	Response at Week 10, Defined as ≥50% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization
Description	PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.
Time Frame	From Randomization to Week 10

Outcome Measure Data

Analysis Population Description

Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Patients randomized into the DBT period with risperidone or olanzapine were analyzed as one arm independent of treatment. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.

Arm/Group Title	Double-blind Treatment (DBT) Period, Lu AF35700 10 mg	DBT Period, Lu AF35700 20 mg	DBT Period, Continued Treatment From PC Period
Arm/Group Description	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 10 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks Lu AF35700: 20 mg/day, encapsulated tablets, orally	Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period Risperidone: 4-6 mg/day, encapsulated tablets, orally Olanzapine: 15-20 mg/day, encapsulated tablets, orally
Measure Participants	201	189	202
Count of Participants [Participants]	10 2.5%	4 1.7%	6 2.6%

Adverse Events

Time Frame	22 weeks
Arm/Group Title	Prospective Confirmation (PC) Period, Risperidone		PC Period, Olanzapine		Double Blind Treatment (DBT) Period, Lu AF35700 10 mg		DBT Period, Lu AF35700 20 mg		DBT Period, Continued Treatment From PC Period
Arm/Group Description	Patients not randomized to double-blind treatment		Patients not randomized to double-blind treatment		Lu AF35700: 10 mg/day, encapsulated tablets, orally for 10 weeks		Lu AF35700: 20 mg/day, encapsulated tablets, orally for 10 weeks		Patients in this arm continued with the same treatment and dose as at the last visit of the PC Period. This arm is analyzed as one single treatment arm independent on which treatment was administered (olanzapine or risperidone).
All Cause Mortality
	Prospective Confirmation (PC) Period, Risperidone		PC Period, Olanzapine		Double Blind Treatment (DBT) Period, Lu AF35700 10 mg		DBT Period, Lu AF35700 20 mg		DBT Period, Continued Treatment From PC Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/708 (0%)		0/384 (0%)		0/234 (0%)		0/232 (0%)		1/230 (0.4%)
Serious Adverse Events
	Prospective Confirmation (PC) Period, Risperidone		PC Period, Olanzapine		Double Blind Treatment (DBT) Period, Lu AF35700 10 mg		DBT Period, Lu AF35700 20 mg		DBT Period, Continued Treatment From PC Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/708 (2%)		7/384 (1.8%)		6/234 (2.6%)		5/232 (2.2%)		5/230 (2.2%)
Cardiac disorders
Myocardial infarction	0/708 (0%)		0/384 (0%)		1/234 (0.4%)		0/232 (0%)		0/230 (0%)
Sinus tachycardia	0/708 (0%)		0/384 (0%)		1/234 (0.4%)		0/232 (0%)		0/230 (0%)
Gastrointestinal disorders
Intestinal haemorrhage	0/708 (0%)		0/384 (0%)		1/234 (0.4%)		0/232 (0%)		0/230 (0%)
General disorders
Vascular stent thrombosis	0/708 (0%)		0/384 (0%)		1/234 (0.4%)		0/232 (0%)		0/230 (0%)
Injury, poisoning and procedural complications
Intentional overdose	0/708 (0%)		0/384 (0%)		0/234 (0%)		0/232 (0%)		1/230 (0.4%)
Investigations
Electrocardiogram abnormal	0/708 (0%)		0/384 (0%)		0/234 (0%)		1/232 (0.4%)		0/230 (0%)
Metabolism and nutrition disorders
Type 2 diabetes mellitus	0/708 (0%)		1/384 (0.3%)		0/234 (0%)		0/232 (0%)		0/230 (0%)
Nervous system disorders
Multiple sclerosis	0/708 (0%)		0/384 (0%)		0/234 (0%)		0/232 (0%)		1/230 (0.4%)
Presyncope	0/708 (0%)		1/384 (0.3%)		0/234 (0%)		0/232 (0%)		0/230 (0%)
Psychiatric disorders
Acute psychosis	1/708 (0.1%)		0/384 (0%)		0/234 (0%)		0/232 (0%)		0/230 (0%)
Hallucination	0/708 (0%)		0/384 (0%)		1/234 (0.4%)		0/232 (0%)		0/230 (0%)
Paranoia	2/708 (0.3%)		1/384 (0.3%)		0/234 (0%)		0/232 (0%)		0/230 (0%)
Psychotic disorder	1/708 (0.1%)		1/384 (0.3%)		0/234 (0%)		1/232 (0.4%)		0/230 (0%)
Schizophrenia	5/708 (0.7%)		1/384 (0.3%)		1/234 (0.4%)		2/232 (0.9%)		2/230 (0.9%)
Suicidal ideation	2/708 (0.3%)		1/384 (0.3%)		2/234 (0.9%)		0/232 (0%)		1/230 (0.4%)
Suicide attempt	0/708 (0%)		0/384 (0%)		0/234 (0%)		0/232 (0%)		1/230 (0.4%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/708 (0%)		0/384 (0%)		0/234 (0%)		1/232 (0.4%)		0/230 (0%)
Pulmonary embolism	1/708 (0.1%)		0/384 (0%)		0/234 (0%)		0/232 (0%)		0/230 (0%)
Pulmonary thrombosis	0/708 (0%)		0/384 (0%)		0/234 (0%)		0/232 (0%)		1/230 (0.4%)
Social circumstances
Social stay hospitalisation	1/708 (0.1%)		1/384 (0.3%)		0/234 (0%)		0/232 (0%)		0/230 (0%)
Surgical and medical procedures
Psychosocial support	1/708 (0.1%)		0/384 (0%)		0/234 (0%)		0/232 (0%)		0/230 (0%)
Vascular disorders
Hypertensive emergency	0/708 (0%)		0/384 (0%)		1/234 (0.4%)		0/232 (0%)		0/230 (0%)
Other (Not Including Serious) Adverse Events
	Prospective Confirmation (PC) Period, Risperidone		PC Period, Olanzapine		Double Blind Treatment (DBT) Period, Lu AF35700 10 mg		DBT Period, Lu AF35700 20 mg		DBT Period, Continued Treatment From PC Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/708 (8.5%)		45/384 (11.7%)		20/235 (8.5%)		40/232 (17.2%)		25/230 (10.9%)
Investigations
Weight increased	5/708 (0.7%)		1/384 (0.3%)		8/235 (3.4%)		19/232 (8.2%)		11/230 (4.8%)
Nervous system disorders
Headache	24/708 (3.4%)		16/384 (4.2%)		11/235 (4.7%)		15/232 (6.5%)		10/230 (4.3%)
Somnolence	34/708 (4.8%)		30/384 (7.8%)		3/235 (1.3%)		9/232 (3.9%)		4/230 (1.7%)
Akathisia	36/708 (5.1%)		8/384 (2.1%)		3/235 (1.3%)		5/232 (2.2%)		4/230 (1.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.