Trial Outcomes & Findings for Study to Evaluate TV-46000 as Maintenance Treatment in Adult and Adolescent Participants With Schizophrenia (NCT NCT03503318)

Last Updated: 2023-03-10

Results Overview

Relapse was defined as 1 or more of the following items: • Clinical Global Impression-Improvement (CGI-I) of ≥5, and - an increase of any of the 4 Positive and Negative Syndrome Scale (PANSS) items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of \>4 with an absolute increase of ≥2 on specific item since randomization, or - an increase in any of the 4 individual PANSS items to a score of \>4 and an absolute increase of ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • Clinical Global Impression-Severity of Suicidality (CGI-SS) of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Data is presented as distribution of relapsing participants (number of participants with impending relapse).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

544 participants

Primary outcome timeframe

From randomization up to 108 weeks

Results posted on

2023-03-10

Participant Flow

Participants were randomized to receive TV-46000 once monthly (q1m) subcutaneous (SC) injections, TV-46000 once every 2 months (q2m) SC injections, or placebo q1m SC injections in a 1:1:1 ratio. Open-label oral risperidone (2 to 5 mg/day) was used to stabilize participants to the treatments (the dose was based on clinical judgment) before randomization.

Participant milestones

Participant milestones
Measure	Placebo Participants received an SC injection of placebo matched to TV-46000 at baseline and every 4 weeks (q4w) thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m Participants received an SC injection of TV-46000 at baseline and every 8 weeks (q8w) thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Overall Study STARTED	181	183	180
Overall Study Received at Least 1 Dose of Study Drug	179	183	180
Overall Study COMPLETED	142	144	140
Overall Study NOT COMPLETED	39	39	40

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received an SC injection of placebo matched to TV-46000 at baseline and every 4 weeks (q4w) thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m Participants received an SC injection of TV-46000 at baseline and every 8 weeks (q8w) thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Overall Study Death	1	0	4
Overall Study Adverse Event	3	4	2
Overall Study Withdrawal by Subject	12	17	16
Overall Study Protocol Violation	5	0	3
Overall Study Lost to Follow-up	17	15	12
Overall Study Other than specified	1	3	3

Baseline Characteristics

Study to Evaluate TV-46000 as Maintenance Treatment in Adult and Adolescent Participants With Schizophrenia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=181 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	Total n=544 Participants Total of all reporting groups
Age, Continuous	49.2 years STANDARD_DEVIATION 11.43 • n=5 Participants	50.6 years STANDARD_DEVIATION 10.30 • n=7 Participants	48.1 years STANDARD_DEVIATION 11.09 • n=5 Participants	49.3 years STANDARD_DEVIATION 10.98 • n=4 Participants
Sex: Female, Male Female	71 Participants n=5 Participants	71 Participants n=7 Participants	70 Participants n=5 Participants	212 Participants n=4 Participants
Sex: Female, Male Male	110 Participants n=5 Participants	112 Participants n=7 Participants	110 Participants n=5 Participants	332 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	42 Participants n=5 Participants	39 Participants n=7 Participants	36 Participants n=5 Participants	117 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	139 Participants n=5 Participants	144 Participants n=7 Participants	144 Participants n=5 Participants	427 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Race · White	68 Participants n=5 Participants	72 Participants n=7 Participants	66 Participants n=5 Participants	206 Participants n=4 Participants
Race/Ethnicity, Customized Race · Black or African American	104 Participants n=5 Participants	108 Participants n=7 Participants	110 Participants n=5 Participants	322 Participants n=4 Participants
Race/Ethnicity, Customized Race · Asian	4 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	7 Participants n=4 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Race · Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race/Ethnicity, Customized Race · Other	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants

PRIMARY outcome

Timeframe: From randomization up to 108 weeks

Population: Intent-to-treat (ITT) analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.

Outcome measures

Outcome measures
Measure	Placebo n=181 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=179 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Time to Impending Relapse (Number of Participants With Impending Relapse) for Intent-to-treat [ITT] Analysis Set	53 Participants	13 Participants	23 Participants

SECONDARY outcome

Timeframe: From randomization up to 108 weeks

Population: eITT analysis set included all participants (adults and adolescents) randomized to the double-blind maintenance stage treatment, regardless if they had received treatment or not.

Relapse was defined as 1 or more of the following items: • CGI-I of ≥5, and - an increase of any of the 4 PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of \>4 with an absolute increase of ≥2 on specific item since randomization, or - an increase in any of the 4 individual PANSS items to a score of \>4 and an absolute increase of ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Data is presented as distribution of relapsing participants (adults and adolescents) (number of participants with impending relapse).

Outcome measures

Outcome measures
Measure	Placebo n=181 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Time to Impending Relapse (Number of Participants With Impending Relapse) for Extended ITT [eITT] Analysis Set	53 Participants	13 Participants	24 Participants

SECONDARY outcome

Timeframe: Week 24

Population: ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.

Relapse was defined as 1 or more of the following items: • CGI-I of ≥5, and - an increase of any of the 4 PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of \>4 with an absolute increase of ≥2 on specific item since randomization, or - an increase in any of the 4 individual PANSS items to a score of \>4 and an absolute increase of ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Impending relapse rate at Week 24 was estimated using the Kaplan-Meier product estimate.

Outcome measures

Outcome measures
Measure	Placebo n=181 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=179 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Proportion of Participants With Impending Relapse	0.28 proportion of participants Interval 0.205 to 0.347	0.07 proportion of participants Interval 0.03 to 0.109	0.11 proportion of participants Interval 0.065 to 0.165

SECONDARY outcome

Timeframe: At the endpoint (up to 108 weeks)

Population: ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.

Stability is defined as meeting all of the following criteria for at least 4 consecutive weeks: outpatient status; PANSS total score ≤80; minimal presence of specific psychotic symptoms on the PANSS, as measured by a score of ≤4 on each of the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content; Clinical Global Impression of Severity (CGI-S) score ≤4 (moderately ill); and CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2. The last valid participant assessment was used as the endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=181 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=179 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Number of Participants Who Maintain Stability at the Endpoint	110 Participants	159 Participants	143 Participants

SECONDARY outcome

Timeframe: At Endpoint (up to 108 weeks)

Population: ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.

The remission was achieved for participants who did not relapse during the study and for over a period of at least 6 months preceding the endpoint, maintained scores of = 3 on each of the 8 specific PANSS items: P1 (delusions), G9 (unusual thought content), P3 (hallucinatory behavior), P2 (conceptual disorganization), G5 (mannerisms/posturing), N1 (blunted affect), N4 (social withdrawal), and N6 (lack of spontaneity). The last valid participant assessment was used as the endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=181 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=179 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Number of Participants Achieving Remission at the Endpoint	30 Participants	39 Participants	42 Participants

SECONDARY outcome

Timeframe: At the Endpoint (up to 108 weeks)

Population: ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.

Relapse was defined as 1 or more of the following items: • CGI-I of ≥5, and - an increase of any of the 4 PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of \>4 with an absolute increase of ≥2 on specific item since randomization, or - an increase in any of the 4 individual PANSS items to a score of \>4 and an absolute increase of ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Observed rate of impending relapse was calculated as the number of participants who relapsed by endpoint divided by the number of participants in each treatment group, using the last valid participant assessment as the endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=181 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=179 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Observed Rate of Impending Relapse (Number of Participants With Impending Relapse) at the Endpoint	53 Participants	13 Participants	23 Participants

SECONDARY outcome

Timeframe: From randomization up to 108 weeks

Population: eITT analysis set included all participants (adults and adolescents) randomized to the double-blind maintenance stage treatment, regardless if they had received treatment or not. Here, 'Overall number of participants analyzed' signifies adolescent participants.

Relapse was defined as 1 or more of the following items: • CGI-I of ≥5, and - an increase of any of the 4 PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score of \>4 with an absolute increase of ≥2 on specific item since randomization, or - an increase in any of the 4 individual PANSS items to a score of \>4 and an absolute increase of ≥4 on combined score of 4 items since randomization; • hospitalization due to worsening of psychotic symptoms; • CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2; • violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. Data is presented as distribution of relapsing participants (adolescents) (number of participants with impending relapse).

Outcome measures

Outcome measures
Measure	Placebo Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=1 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Time to Impending Relapse (Number of Participants With Impending Relapse) in the Adolescent Participants	—	—	1 Participants

SECONDARY outcome

Timeframe: Baseline, endpoint and end of treatment (up to Week 108)

Population: ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure, 'Number analyzed' signifies participants evaluable at specified timepoint.

The DAI-10 is a 10-item questionnaire to assess 1) subjective experience of drug and 2) attitudes and beliefs toward neuroleptics which may influence compliance in schizophrenia participants. The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a participant who was fully adherent to the prescribed medication answered as "True" and 4 items (2, 5, 6, and 8) that a participant who was fully adherent to the prescribed medication answered as "False." A correct answer was scored +1 and an incorrect answer was scored -1. The total score was the sum of pluses and minuses, which ranged from -10 to 10 in increments of 2. A positive total score indicated a positive subjective response (compliant) and a negative total score indicated a negative subjective response (non-compliance). Higher scores denoted better compliance. The last valid participant assessment was used as the endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=178 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=182 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=179 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Change From Baseline in Drug Attitudes Inventory 10-item Version (DAI-10) Total Score at the Endpoint and End of Treatment Baseline	6.1 units on a scale Standard Deviation 3.23	5.8 units on a scale Standard Deviation 3.63	5.7 units on a scale Standard Deviation 3.13
Change From Baseline in Drug Attitudes Inventory 10-item Version (DAI-10) Total Score at the Endpoint and End of Treatment Change at the Endpoint	-0.8 units on a scale Standard Deviation 3.88	0.1 units on a scale Standard Deviation 3.34	-0.3 units on a scale Standard Deviation 3.65
Change From Baseline in Drug Attitudes Inventory 10-item Version (DAI-10) Total Score at the Endpoint and End of Treatment Change at the End of Treatment	-0.9 units on a scale Standard Deviation 3.42	0.3 units on a scale Standard Deviation 2.84	0.3 units on a scale Standard Deviation 3.51

SECONDARY outcome

Timeframe: Baseline, endpoint and end of treatment (up to Week 108)

The SQLS comprises 33 items categorized in 2 domains: psychosocial feelings (20 items) and cognition and vitality (13 items). The items were scored on a 5-point scale (1 - never, 2 - rarely, 3 - sometimes, 4 - often, 5 - always). Individual domain and total scores were standardized by scoring algorithm to a 0 (best health status) to 100 (worst health status) scale, with higher scores indicating comparatively lower quality of life. The last valid participant assessment was used as the endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=178 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=182 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=179 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Change From Baseline in Schizophrenia Quality of Life Scale (SQLS) Total Score at the Endpoint and End of Treatment Baseline	34.0 units on a scale Standard Deviation 16.06	33.1 units on a scale Standard Deviation 16.79	34.2 units on a scale Standard Deviation 15.70
Change From Baseline in Schizophrenia Quality of Life Scale (SQLS) Total Score at the Endpoint and End of Treatment Change at the Endpoint	0.9 units on a scale Standard Deviation 14.24	-4.5 units on a scale Standard Deviation 14.31	-4.1 units on a scale Standard Deviation 15.23
Change From Baseline in Schizophrenia Quality of Life Scale (SQLS) Total Score at the Endpoint and End of Treatment Change at the End of Treatment	-2.3 units on a scale Standard Deviation 13.26	-7.2 units on a scale Standard Deviation 13.79	-7.3 units on a scale Standard Deviation 12.30

SECONDARY outcome

Timeframe: From randomization up to 120 days after last dose of study drug (up to Week 125)

Population: Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo.

An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring after the first dose of the study drug until 120 days after the last dose of study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	92 Participants	111 Participants	121 Participants

SECONDARY outcome

Timeframe: Baseline, end of treatment (up to 108 weeks)

Population: Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'Number analyzed' signifies participants evaluable at specified timepoint.

The AIMS is a 14-item scale that includes assessments of orofacial movements, extremity and truncal dyskinesia, examiner's judgment of global severity, subjective measures of awareness of movements and distress, and a yes/no assessment of problems concerning teeth and/or dentures. Total AIMS score is a sum of item 1 through 7. Items 1 through 7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 0 (no dyskinesia) to 4 (severe dyskinesia) scale. Total AIMS score for Items 1-7 ranged from 0 to 28; with higher scores indicating greater severity of the condition.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Change From Baseline in Total Abnormal Involuntary Movement Scale (AIMS) Score at the End of Treatment Baseline	0.4 units on a scale Standard Deviation 1.30	0.5 units on a scale Standard Deviation 1.83	0.2 units on a scale Standard Deviation 0.79
Change From Baseline in Total Abnormal Involuntary Movement Scale (AIMS) Score at the End of Treatment Change at the End of Treatment	0.0 units on a scale Standard Deviation 1.10	0.1 units on a scale Standard Deviation 0.62	0.1 units on a scale Standard Deviation 1.00

SECONDARY outcome

Timeframe: Baseline, end of treatment (up to 108 weeks)

The SAS is a 10-item instrument for the assessment of neuroleptic-induced parkinsonism. The items on the scale include measurements of hypokinesia, rigidity, glabellar reflex, tremor, and salivation. Each item was rated on a 5-point scale (0 \[None/Normal\] to 4 \[Extreme/Severe\]). The mean score was calculated by adding the individual item scores and dividing by 10. The total mean score ranged from 0-4, with a higher score indicating greater severity of symptoms.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Change From Baseline in Simpson-Angus Scale (SAS) Mean Score at the End of Treatment Baseline	0.07 units on a scale Standard Deviation 0.137	0.09 units on a scale Standard Deviation 0.195	0.06 units on a scale Standard Deviation 0.134
Change From Baseline in Simpson-Angus Scale (SAS) Mean Score at the End of Treatment Change at the End of Treatment	0.04 units on a scale Standard Deviation 0.134	0.02 units on a scale Standard Deviation 0.211	0.00 units on a scale Standard Deviation 0.102

SECONDARY outcome

Timeframe: Baseline, end of treatment (up to 108 weeks)

The BARS is an instrument that assesses the severity of drug-induced akathisia. The BARS includes 3 items for rating objective restless movements, subjective restlessness, and any subjective distress associated with akathisia that were scored on a 4-point scale of 0 (normal/no distress) to 3 (constant restlessness/severe distress). Total score was the sum of scores of each item and ranged from 0-9, with higher scores indicating greater severity of akathisia.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Change From Baseline in Total Barnes Akathisia Rating Scale (BARS) Score at the End of Treatment Baseline	0.2 units on a scale Standard Deviation 0.63	0.1 units on a scale Standard Deviation 0.39	0.2 units on a scale Standard Deviation 0.57
Change From Baseline in Total Barnes Akathisia Rating Scale (BARS) Score at the End of Treatment Change at the End of Treatment	-0.1 units on a scale Standard Deviation 0.56	0.0 units on a scale Standard Deviation 0.51	-0.1 units on a scale Standard Deviation 0.56

SECONDARY outcome

Timeframe: Baseline, post-baseline (up to 108 weeks)

Population: Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo.

The C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Number of Participants Reporting Suicidal Behavior and Suicidal Ideation Using Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline and Post-Baseline Baseline: Suicidal behavior	0 Participants	0 Participants	3 Participants
Number of Participants Reporting Suicidal Behavior and Suicidal Ideation Using Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline and Post-Baseline Baseline: Suicidal ideation	6 Participants	5 Participants	7 Participants
Number of Participants Reporting Suicidal Behavior and Suicidal Ideation Using Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline and Post-Baseline Post-baseline: Suicidal behavior	3 Participants	1 Participants	1 Participants
Number of Participants Reporting Suicidal Behavior and Suicidal Ideation Using Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline and Post-Baseline Post-baseline: Suicidal ideation	12 Participants	7 Participants	12 Participants

SECONDARY outcome

Timeframe: Baseline, end of treatment (up to 108 weeks)

The CDSS is specifically designed to assess the level of depression separate from the positive, negative, and EPS in schizophrenia. This clinician-administered instrument consists of 9 items, each rated on a 4-point scale from 0 (absent) to 3 (severe) that were added together to form the total CDSS depression score of the participant. The total score ranged from 0-27, with higher scores indicating greater severity of the condition.

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Change From Baseline in Calgary Depression Scale for Schizophrenia (CDSS) Score at the End of Treatment Baseline	1.6 units on a scale Standard Deviation 2.14	1.3 units on a scale Standard Deviation 1.92	1.5 units on a scale Standard Deviation 1.93
Change From Baseline in Calgary Depression Scale for Schizophrenia (CDSS) Score at the End of Treatment Change at the End of Treatment	-0.4 units on a scale Standard Deviation 2.72	-0.3 units on a scale Standard Deviation 1.39	-0.8 units on a scale Standard Deviation 2.24

SECONDARY outcome

Timeframe: Baseline, end of treatment (up to 108 weeks)

Population: Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure, 'Number analyzed' signifies participants evaluable at specified timepoint.

The CGI-SS scale provides an overall clinician-rated assessment of the risk of suicidality. The CGI-SS consists of a 5-point scale in Part 1 (the most severe level of suicidality experience) ranging from 1 (not at all suicidal) to 5 (attempted suicide) and a 7-point scale in Part 2 (change in participant suicidality) ranging from 1 (very much improved) to 7 (very much worse).

Outcome measures

Outcome measures
Measure	Placebo n=179 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=179 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Change From Baseline in Clinical Global Impression-Severity of Suicidality (CGI-SS) Score at the End of Treatment The most severe level of suicidality experience at Baseline	1.0 units on a scale Standard Deviation 0.00	1.0 units on a scale Standard Deviation 0.00	1.0 units on a scale Standard Deviation 0.00
Change From Baseline in Clinical Global Impression-Severity of Suicidality (CGI-SS) Score at the End of Treatment Change in participant suicidality at the End of Treatment	4.0 units on a scale Standard Deviation 0.00	4.0 units on a scale Standard Deviation 0.00	4.0 units on a scale Standard Deviation 0.00

SECONDARY outcome

Timeframe: 1 hour prior to dosing at Baseline (Day 1) and at the end of treatment visit (up to 108 weeks)

Population: Pharmacokinetics (PK) analysis set included all randomized participants who received ≥1 dose of study treatment or placebo and who also had ≥1 plasma concentration measured. Here, 'Number analyzed' signifies participants evaluable for specified categories.

Outcome measures

Outcome measures
Measure	Placebo n=178 Participants Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=178 Participants Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=177 Participants Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone) Risperidone at Baseline	4.694 ng/mL Interval 0.05 to 58.376	6.452 ng/mL Interval 0.05 to 97.935	5.364 ng/mL Interval 0.05 to 125.524
Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone) Risperidone at the End of Treatment	1.323 ng/mL Interval 0.05 to 47.683	13.215 ng/mL Interval 0.05 to 136.184	8.838 ng/mL Interval 0.05 to 75.95
Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone) 9-OH-Risperidone at Baseline	14.965 ng/mL Interval 0.15 to 84.471	18.473 ng/mL Interval 0.15 to 105.26	15.187 ng/mL Interval 0.15 to 107.316
Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone) 9-OH-Risperidone at the End of Treatment	2.982 ng/mL Interval 0.15 to 40.73	26.202 ng/mL Interval 0.15 to 101.354	17.778 ng/mL Interval 0.15 to 88.333
Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone) Total Active Moiety at Baseline	19.060 ng/mL Interval 0.05 to 95.595	24.200 ng/mL Interval 0.05 to 134.202	19.945 ng/mL Interval 0.05 to 172.763
Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone) Total Active Moiety at the End of Treatment	4.078 ng/mL Interval 0.05 to 62.621	38.429 ng/mL Interval 0.05 to 159.498	25.947 ng/mL Interval 0.05 to 135.823

Adverse Events

Placebo

Serious events: 14 serious events

Other events: 35 other events

Deaths: 1 deaths

TV-46000 q1m

Serious events: 8 serious events

Other events: 49 other events

Deaths: 0 deaths

TV-46000 q2m

Serious events: 10 serious events

Other events: 48 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=179 participants at risk Participants received an SC injection of placebo matched to TV-46000 at baseline and q4w thereafter. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q1m n=183 participants at risk Participants received an SC injection of TV-46000 at baseline and q4w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.	TV-46000 q2m n=180 participants at risk Participants received an SC injection of TV-46000 at baseline and q8w thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter. The maximal dose administered to adult participants was comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents was comparable to 4 mg/day. Participants continued treatment until they experienced a relapse event; met 1 or more of the study discontinuation or withdrawal criteria; or remained relapse-free during the double-blind phase until the study was terminated.
General disorders Injection site nodule	3.4% 6/179 • Number of events 20 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	6.6% 12/183 • Number of events 29 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	7.2% 13/180 • Number of events 23 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.
General disorders Injection site pain	6.1% 11/179 • Number of events 37 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	4.9% 9/183 • Number of events 13 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	6.7% 12/180 • Number of events 14 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.
General disorders Injection site pruritus	2.2% 4/179 • Number of events 5 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	5.5% 10/183 • Number of events 17 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	3.9% 7/180 • Number of events 10 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.
Investigations Weight increased	3.4% 6/179 • Number of events 6 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	5.5% 10/183 • Number of events 10 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	7.2% 13/180 • Number of events 14 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.
Nervous system disorders Headache	5.6% 10/179 • Number of events 11 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	4.9% 9/183 • Number of events 10 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	6.1% 11/180 • Number of events 11 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.
Psychiatric disorders Insomnia	5.6% 10/179 • Number of events 11 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	6.6% 12/183 • Number of events 13 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.	2.8% 5/180 • Number of events 6 • From randomization up to 120 days after last dose of study drug (up to Week 125) Safety analysis set included only the randomized participants who received ≥1 dose of study treatment or placebo. No study drug was administered during the open-label stabilization period. All treatment-emergent adverse events are presented.

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products R&D, Inc.

Phone: 1-888-483-8279

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
Publication restrictions are in place

Restriction type: OTHER