Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Risperidone Extended-Release Injectable Suspension (TV-46000) for Subcutaneous Use as Maintenance Treatment in Adult and Adolescent Patients with Schizophrenia
Summary
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EudraCT number |
2018-001619-65 |
Trial protocol |
BG |
Global end of trial date |
03 Dec 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jun 2021
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First version publication date |
20 Jun 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TV46000-CNS-30072
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03503318 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Teva Branded Pharmaceutical Products, R&D Inc.
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Sponsor organisation address |
145 Brandywine Parkway, West Chester, United States, 19380
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Dec 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Sep 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Dec 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to evaluate the efficacy of TV-46000 during maintenance treatment in adult participants with schizophrenia.
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Protection of trial subjects |
This study was conducted in full accordance with the International Conference on Harmonisation Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Apr 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 63
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Country: Number of subjects enrolled |
United States: 481
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Worldwide total number of subjects |
544
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EEA total number of subjects |
63
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
530
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From 65 to 84 years |
13
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
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 1:1:1 ratio. Open-label oral risperidone (2 to 5 mg/day) was used to stabilize participants to the treatments (dose was based on clinical judgment) before randomization. | ||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
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. | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo matched to TV-46000 was administered per dose and schedule specified in the arm description.
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Arm title
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TV-46000 q1m | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
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. | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
TV-46000
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Investigational medicinal product code |
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Other name |
Risperidone
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
TV-46000 was administered per dose and schedule specified in the arm description.
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Arm title
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TV-46000 q2m | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
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. | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo matched to TV-46000 was administered per dose and schedule specified in the arm description.
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Investigational medicinal product name |
TV-46000
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Investigational medicinal product code |
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Other name |
Risperidone
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
TV-46000 was administered per dose and schedule specified in the arm description.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TV-46000 q1m
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TV-46000 q2m
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
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. | ||
Reporting group title |
TV-46000 q1m
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Reporting group description |
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. | ||
Reporting group title |
TV-46000 q2m
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Reporting group description |
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. |
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End point title |
Number of Participants With Impending Relapse (Intent-to-treat [ITT] Analysis Set) | ||||||||||||
End point description |
Relapse was defined as 1 or more of following items: • Clinical Global Impression–Improvement (CGI-I) of ≥5, and - an increase of any of 4 Positive and Negative Syndrome Scale (PANSS) items: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content, to a score >4 with an absolute increase of ≥2 on specific item or ≥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). ITT analysis set: adult participants randomized to double-blind maintenance treatment, regardless if they received treatment or not.
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End point type |
Primary
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End point timeframe |
From randomization up to 108 weeks
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Analysis was performed using the stratified Cox proportional hazard model, with treatment (placebo, TV-46000 q1m and TV-46000 q2m or placebo and TV-46000 overall [including q1m and q2m]) as explanatory variable and sex-dose as a stratification factor, and the stratified log rank test p-value (sex-dose as a stratification factor) referred to (TV-46000/placebo) comparison.
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Comparison groups |
Placebo v TV-46000 q1m
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Number of subjects included in analysis |
364
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
< 0.0001 [1] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.2
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.109 | ||||||||||||
upper limit |
0.367 | ||||||||||||
Notes [1] - Threshold for significance at 0.05 level. |
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||
Statistical analysis description |
Analysis was performed using the stratified Cox proportional hazard model, with treatment (placebo, TV-46000 q1m and TV-46000 q2m or placebo and TV-46000 overall [including q1m and q2m]) as explanatory variable and sex-dose as a stratification factor, and the stratified log rank test p-value (sex-dose as a stratification factor) referred to (TV-46000/placebo) comparison.
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Comparison groups |
Placebo v TV-46000 q2m
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Number of subjects included in analysis |
360
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.375
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.227 | ||||||||||||
upper limit |
0.618 | ||||||||||||
Notes [2] - Threshold for significance at 0.05 level. |
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End point title |
Number of Participants With Impending Relapse (Extended ITT [eITT] Analysis Set) | ||||||||||||
End point description |
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 >4 with an absolute increase of ≥2 on specific item or ≥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). 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.
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End point type |
Secondary
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End point timeframe |
From randomization up to 108 weeks
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No statistical analyses for this end point |
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End point title |
Proportion of Participants With Impending Relapse | ||||||||||||||||
End point description |
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 >4 with an absolute increase of ≥2 on specific item or ≥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. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.
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End point type |
Secondary
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End point timeframe |
Week 24
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No statistical analyses for this end point |
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End point title |
Number of Participants Who Maintain Stability at the Endpoint | ||||||||||||
End point description |
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. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.
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End point type |
Secondary
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End point timeframe |
At the endpoint (up to 108 weeks)
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No statistical analyses for this end point |
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End point title |
Number of Participants Achieving Remission at the Endpoint | ||||||||||||
End point description |
The remission was achieved for participants that did not relapse during the study and in addition, 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. The participant population was limited to treated by the study drug for at least 6 months. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they had received treatment or not.
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End point type |
Secondary
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End point timeframe |
At Endpoint (up to 108 weeks)
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No statistical analyses for this end point |
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End point title |
Observed Rate of Impending Relapse (Number of Participants With Impending Relapse) at the Endpoint | ||||||||||||
End point description |
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 >4 with an absolute increase of ≥2 on specific item or ≥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. ITT analysis set: adult participants randomized to double-blind maintenance treatment, regardless if they received treatment or not.
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End point type |
Secondary
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End point timeframe |
At the Endpoint (up to 108 weeks)
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No statistical analyses for this end point |
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End point title |
Time to Impending Relapse (Number of Participants With Impending Relapse) in the Adolescent Participants | ||||||||||||
End point description |
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 >4 with an absolute increase of ≥2 on specific item or ≥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). eITT analysis set: all participants (adults and adolescents) randomized to the double-blind maintenance stage treatment, regardless if they received treatment or not. Here, 'Overall number of participants analysed' = adolescent participants.
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End point type |
Secondary
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End point timeframe |
From randomization up to 108 weeks
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Notes [3] - There were no adolescent participants in this arm. [4] - There were no adolescent participants in this arm. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Drug Attitudes Inventory 10-item Version (DAI-10) Total Score at the Endpoint and End of Treatment | ||||||||||||||||||||||||||||
End point description |
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. ITT analysis set included adult participants randomized to the double-blind maintenance treatment, regardless if they received treatment or not. Here, 'Overall number of participants analysed' = participants evaluable for this endpoint, 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, endpoint and end of treatment (up to Week 108)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Schizophrenia Quality of Life Scale (SQLS) Total Score at the Endpoint and End of Treatment | ||||||||||||||||||||||||||||
End point description |
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. 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 analysed' signifies participants evaluable for this endpoint, 'n' signifies participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, endpoint and end of treatment (up to Week 108)
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No statistical analyses for this end point |
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End point title |
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ||||||||||||
End point description |
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. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo.
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End point type |
Secondary
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End point timeframe |
From randomization up to 120 days after last dose of study drug (up to Week 125)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Total Abnormal Involuntary Movement Scale (AIMS) Score at the End of Treatment | ||||||||||||||||||||||||
End point description |
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. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, n' signifies participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, end of treatment (up to 108 weeks)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Simpson-Angus Scale (SAS) Mean Score at the End of Treatment | ||||||||||||||||||||||||
End point description |
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 0-40, with a higher score indicating greater severity of symptoms. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'n' signifies participants evaluable at specified timepoint.
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End point type |
Secondary
|
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End point timeframe |
Baseline, end of treatment (up to 108 weeks)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Total Barnes Akathisia Rating Scale (BARS) Score at the End of Treatment | ||||||||||||||||||||||||
End point description |
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. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'n' signifies participants evaluable at specified timepoint.
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End point type |
Secondary
|
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End point timeframe |
Baseline, end of treatment (up to 108 weeks)
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No statistical analyses for this end point |
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End point title |
Number of Participants Reporting Suicidal Behavior and Suicidal Ideation Using Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline and Post-Baseline | ||||||||||||||||||||||||||||
End point description |
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. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo.
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End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Baseline, post-baseline (up to 108 weeks)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Calgary Depression Scale for Schizophrenia (CDSS) Score at the End of Treatment | ||||||||||||||||||||||||
End point description |
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. Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'n' signifies participants evaluable at specified timepoint.
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End point type |
Secondary
|
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End point timeframe |
Baseline, end of treatment (up to 108 weeks)
|
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Clinical Global Impression-Severity of Suicidality (CGI-SS) Score at the End of Treatment | ||||||||||||||||||||||||
End point description |
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). Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo. Here, 'Overall number of participants analysed' signifies participants evaluable for this endpoint, 'n' signifies participants evaluable at specified timepoint.
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End point type |
Secondary
|
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End point timeframe |
Baseline, end of treatment (up to 108 weeks)
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No statistical analyses for this end point |
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End point title |
Plasma Concentration of Risperidone, 9-OH-risperidone, and Total Active Moiety (Sum of Risperidone and 9-OH-risperidone) | ||||||||||||||||||||||||||||||||||||||||
End point description |
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 analysed' signifies participants evaluable for specified categories.
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End point type |
Secondary
|
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End point timeframe |
1 hour prior to dosing at Baseline (Day 1) and at the end of treatment (EOT) visit (up to 108 weeks)
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From randomization up to 120 days after last dose of study drug (up to Week 125)
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Adverse event reporting additional description |
Safety analysis set included all randomized participants who received ≥1 dose of study treatment or placebo.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TV-46000 q2m
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TV-46000 q1m
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Notes [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal. Justification: This is a gender-specific AE that affects only female participants |
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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06 Dec 2018 |
The following major procedural changes (not all-inclusive) were made to the protocol:
• various revisions due to the introduced possibility of enrolling adolescent participants (including eligibility criteria, maximum dose to be administered, up to 3 additional PK samples to be collected from adolescents)
• urine pregnancy test was added to the baseline visit clarification which scales were only performed in adult participants
• definition of study completers added
• clarification that collection of the unscheduled PK samples is only relevant for Stage 2
• clarification regarding blinding per updated sponsor template to enhance participant safety and ensure that the participant’s needs are first addressed
• correction of blood volumes per updated laboratory manual
• clarification regarding a positive urine drug screen result due to the high prevalence of recreational and medical use of various substances in this participant population. |
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16 Oct 2019 |
The following major procedural changes (not all-inclusive) were made to the protocol:
• in addition to the originally planned, single interim analysis that was to be conducted when 125 relapse events were observed, an earlier interim analysis (when 90 relapse events were reached) was introduced
• prolongation of study duration (although in case of a successful interim analysis, the study would be terminated earlier)
• change of inclusion criterion to omit the body mass index (BMI) percentile limitation
• updates to the planned number of enrolled participants per updated projections
• clarification of procedures to be performed during unscheduled visits
• updates to vendor information and personnel details following changes of responsibilities
• clarification regarding highly effective birth control methods (that is, only highly effective birth control methods should have been used in this study). |
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19 Apr 2020 |
The following major procedural changes (not all-inclusive) were made to the protocol:
• changes to various sections due to the planned earlier final analysis
• change of responsibilities in the sponsor's medical expert
• blood volumes updated to reflect longer treatment duration in Stage 2 of the study
• COVID-19 pandemic-related operational updates and contingency measures were added to the study as a new appendix. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |