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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-arm Study to Assess the Efficacy, Safety, and Tolerability of AVP-786 (Deudextromethorphan hydrobromide [d6-DM]/Quinidine sulfate [Q]) for the Treatment of Negative Symptoms of Schizophrenia

    Summary
    EudraCT number
    		 2021-001352-33
    Trial protocol
    		 BG   PL   ES  
    Global end of trial date
    23 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jun 2024
    First version publication date
    15 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    18-AVP-786-207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03896945
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 124525
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Blvd, Rockville, United States, 20850
    Public contact
    Agitation Project Team, Otsuka Pharmaceutical Development & Commercialization, Inc., 585 319 7969, chirag.savla@otsuka-us.com
    Scientific contact
    Agitation Project Team, Otsuka Pharmaceutical Development & Commercialization, Inc., 585 319 7969, chirag.savla@otsuka-us.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety, and tolerability of AVP-786, as compared with placebo, for the treatment of negative symptoms of schizophrenia.
    Protection of trial subjects
    Each subject signed an informed consent form (ICF) before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Feb 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Bulgaria: 27
    Country: Number of subjects enrolled
    United States: 104
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Worldwide total number of subjects
    136
    EEA total number of subjects
    31
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    136
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in this study at 65 investigative sites in Bulgaria, Poland, and the United States including Puerto Rico from 15 February 2019 to 23 May 2023.

    Pre-assignment
    Screening details
    		 Subjects with schizophrenia were enrolled in Phase A: Placebo run-in period. On completing Phase A, subjects were randomised in a 1:1 ratio in Phase B: Double-blind treatment (DBT) period to receive AVP-786/placebo. In Phase A, subjects were classified as placebo responders & non-responders. Placebo responders were excluded from efficacy analysis.

    Period 1
    Period 1 title
    Phase A: Placebo Run-in Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Arm title
    		 Placebo (Run-in Period)
    Arm description
    		 Subjects received AVP-786 matching placebo capsules, orally, twice a day (BID) over a 3-week run-in period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral capsules, BID during 3-week run-in period.

    Number of subjects in period 1
    		Placebo (Run-in Period)
    Started
    136
    Placebo Responders
    10 [1]
    Placebo Non-Responders
    115 [2]
    Completed
    125
    Not completed
    11
         Non-compliance
    1
         Withdrawal by Subject
    4
         Lost to follow-up
    2
         Reason not Specified
    3
         Protocol deviation
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The participants who completed the Placebo Run-in Period (Phase A) were only classified as placebo responder or non-responders. Hence, the number reported for this milestone is less than the total number of participants who were enrolled in the study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The participants who completed the Placebo Run-in Period (Phase A) were only classified as placebo responder or non-responders. Hence, the number reported for this milestone is less than the total number of participants who were enrolled in the study.
    Period 2
    Period 2 title
    Phase B: Double-blind Treatment Period
    Is this the baseline period?
    		 Yes [3]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AVP-786
    Arm description
    		 Subjects received AVP-786-28/4.9 (deudextromethorphan hydrobromide (d6-DM) 28 milligrams (mg)/quinidine sulfate (Q) 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, once daily (QD) for 3 days followed by AVP-786-28/4.9 capsule, orally, BID for the next 4 days of titration period. Following the 1-week titration period, subjects received AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg), orally, BID for the remaining 11 weeks of the DBT period. 
    Arm type
    		 Experimental

    Investigational medicinal product name
    AVP-786
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral capsules, QD for 3 days followed by BID for the next 4 days. Following 1 week titration, BID for the remaining 11 weeks of the DBT period. 

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral capsules, QD for 3 days.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received AVP-786 matching placebo capsules, orally, BID over a 12-week DBT period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral capsules, BID during 12-week DBT period.

    Notes
    [3] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Participants who completed the Placebo run-in period (Phase A) were considered to be randomized in the study. All participants completing Phase A started the DBT period (Phase B). Hence, Phase B was considered to be the baseline period.
    Number of subjects in period 2 [4]
    		AVP-786 Placebo
    Started
    65
    60
    Completed
    57
    52
    Not completed
    8
    8
         Noncompliance with Study Drug
    -
    2
         Physician decision
    1
    -
         Adverse Event
    2
    -
         Withdrawal by Subject
    3
    4
         Study Terminated by Sponsor
    -
    1
         Protocol deviation
    2
    -
         Lack of efficacy
    -
    1
    Notes
    [4] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Only the subjects randomized in the Double-blind Treatment Period were analyzed for baseline characteristics.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AVP-786
    Reporting group description
    		 Subjects received AVP-786-28/4.9 (deudextromethorphan hydrobromide (d6-DM) 28 milligrams (mg)/quinidine sulfate (Q) 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, once daily (QD) for 3 days followed by AVP-786-28/4.9 capsule, orally, BID for the next 4 days of titration period. Following the 1-week titration period, subjects received AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg), orally, BID for the remaining 11 weeks of the DBT period. 

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received AVP-786 matching placebo capsules, orally, BID over a 12-week DBT period.

    Reporting group values
    		 AVP-786 Placebo Total
    Number of subjects
    		 65 60 125
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.8 ± 9.54 44.0 ± 10.25 -
    Gender categorical
    Units: Subjects
        Female
    		 20 24 44
        Male
    		 45 36 81
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 7 13
        Not Hispanic or Latino
    		 42 40 82
        Unknown or Not Reported
    		 17 13 30
    Race
    Units: Subjects
        White
    		 14 12 26
        Black or African American
    		 33 34 67
        Asian
    		 1 0 1
        Other
    		 0 1 1
        Missing
    		 17 13 30
    Patient Global Impression of Change (PGI-C) Score
    The PGI-C is 7-point (1-7) subject-rated scale used to assess treatment response with respect to schizophrenia as follows: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, or 7=very much worse. Missing PGI-C rating was not imputed. Modified Intent-To-Treat (mITT) population included all subjects who were placebo run-in nonresponders, randomised in Phase B and in the safety population with both Phase B baseline and at least 1 postbaseline PANSS measurement.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 ± ± -
    Subject analysis sets

    Subject analysis set title
    AVP-786
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects received AVP-786-28/4.9 (d6-DM 28 mg/Q 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, QD for 3 days followed by AVP-786-28/4.9 capsule, orally, BID for the next 4 days of titration period. Following the 1-week titration period, subjects received AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg), orally, BID for the remaining 11 weeks of the DBT period. 

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects received AVP-786 matching placebo capsules, orally, BID over a 12-week DBT period.

    Subject analysis sets values
    		 AVP-786 Placebo
    Number of subjects
    61
    54
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race
    Units: Subjects
        White
        Black or African American
        Asian
        Other
        Missing
    Patient Global Impression of Change (PGI-C) Score
    The PGI-C is 7-point (1-7) subject-rated scale used to assess treatment response with respect to schizophrenia as follows: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, or 7=very much worse. Missing PGI-C rating was not imputed. Modified Intent-To-Treat (mITT) population included all subjects who were placebo run-in nonresponders, randomised in Phase B and in the safety population with both Phase B baseline and at least 1 postbaseline PANSS measurement.
    Units: score on a scale
        arithmetic mean (standard deviation)
    3.3 ± 0.91
    3.5 ± 0.86

    End points

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    End points reporting groups
    Reporting group title
    Placebo (Run-in Period)
    Reporting group description
    		 Subjects received AVP-786 matching placebo capsules, orally, twice a day (BID) over a 3-week run-in period.
    Reporting group title
    AVP-786
    Reporting group description
    		 Subjects received AVP-786-28/4.9 (deudextromethorphan hydrobromide (d6-DM) 28 milligrams (mg)/quinidine sulfate (Q) 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, once daily (QD) for 3 days followed by AVP-786-28/4.9 capsule, orally, BID for the next 4 days of titration period. Following the 1-week titration period, subjects received AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg), orally, BID for the remaining 11 weeks of the DBT period. 

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received AVP-786 matching placebo capsules, orally, BID over a 12-week DBT period.

    Subject analysis set title
    AVP-786
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects received AVP-786-28/4.9 (d6-DM 28 mg/Q 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, QD for 3 days followed by AVP-786-28/4.9 capsule, orally, BID for the next 4 days of titration period. Following the 1-week titration period, subjects received AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg), orally, BID for the remaining 11 weeks of the DBT period. 

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects received AVP-786 matching placebo capsules, orally, BID over a 12-week DBT period.

    Primary: Change From Baseline (Week 3) to Week 15 in the Positive and Negative Syndrome Scale (PANSS) Marder Negative Factors Score

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    End point title
    		 Change From Baseline (Week 3) to Week 15 in the Positive and Negative Syndrome Scale (PANSS) Marder Negative Factors Score
    End point description
    PANSS consists of 3 subscales: a total of 30 disparate items. Each item's severity was rated on 7-point scale, with 1=absence of symptoms & 7=extremely severe symptoms. PANSS marder negative factors score comprises 7 items of 30-item PANSS: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity &flow of conversation, motor retardation &active social avoidance. PANSS Negative Subscale score range is 7=absence of symptoms to 49=extremely severe symptoms. PANSS total score range=30-210, higher scores=more severe symptoms. Negative change from baseline=improvement. Baseline=end of placebo run-in period (Week 3) & the last assessment prior to first dose of study drug. mITT population=all subjects who were placebo run-in nonresponders, randomised in Phase B & in safety population with both Phase B baseline & at least 1 postbaseline PANSS measurement.
    End point type
    Primary
    End point timeframe
    Baseline (Week 3); Week 15
    End point values
    		 AVP-786 Placebo
    Number of subjects analysed
    61
    54
    Units: score on a scale
        least squares mean (standard error)
    -2.3 ± 0.47
    -2.5 ± 0.49
    Statistical analysis title
    		 PANSS Marder Negative Factors Score
    Comparison groups
    AVP-786 v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.768 [1]
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 1.47
    Notes
    [1] - The MMRM analysis included fixed effects for treatment, trial centre, visit, treatment-by-visit interaction, and baseline-by-visit interaction. An unstructured covariance model was used.

    Secondary: Change From Baseline (Week 3) to Week 15 in the Negative Symptom Assessment-16 (NSA-16) Global Negative Symptom Score

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    End point title
    		 Change From Baseline (Week 3) to Week 15 in the Negative Symptom Assessment-16 (NSA-16) Global Negative Symptom Score
    End point description
    NSA-16 consists of 16 items & uses 5-factor model to describe negative symptoms:communication(1-4)range=4-24, emotional/affective(5-7)range=3-18,social involvement(8-10)range=3-18,motivational(11-14)range=4-24,&retardation(15&16)range=3-18,&Global Negative Symptom Rating.Items are rated on 6-point scale, 1=behaviour is normal to 6=behaviour severely reduced.Each item admits score of 9 if item is not ratable.Global Negative Symptom Rating range is 1=no evidence of symptoms to 7=extremely severe symptoms.16 items total score range=16-96, higher score=greater clinical severity of symptoms & global rating scale range=1-7, higher score=extremely severe symptoms.If >3 items were not ratable,total score unevaluable & was regarded as missing. Negative change from baseline=improvement. mITT population=all placebo run-in nonresponders,randomised in Phase B (safety population), had Phase B baseline &at least 1 postbaseline PANSS.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 3); Week 15
    End point values
    		 AVP-786 Placebo
    Number of subjects analysed
    61
    54
    Units: score on a scale
        least squares mean (standard error)
    -0.4 ± 0.10
    -0.5 ± 0.10
    Statistical analysis title
    		 NSA-16 Global Negative Symptom Score
    Comparison groups
    AVP-786 v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.443 [2]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.37
    Notes
    [2] - The MMRM analysis included fixed effects for treatment, trial centre, visit, treatment-by-visit interaction, and baseline-by-visit interaction. An unstructured covariance model was used.

    Secondary: Change From Baseline (Week 3) to Week 15 in the Patient Global Impression of Severity (PGI-S) Score

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    End point title
    		 Change From Baseline (Week 3) to Week 15 in the Patient Global Impression of Severity (PGI-S) Score
    End point description
    The severity of subjects' illness with respect to their schizophrenia was rated using a 7-point PGI-S. PGI-S scores range from 1 to 7, where 1= normal, not at all ill, 2= borderline ill, 3=mildly ill, 4=moderately ill, 5= markedly ill, 6=severely ill, 7=extremely ill. Missing PGI-S rating were not imputed. Negative change from baseline indicates improvement. Baseline is defined as the end of the placebo run-in period (Week 3), and to be the last assessment prior to the first dose of study drug. mITT population included all subjects who were placebo run-in nonresponders, randomised in Phase B and in the safety population with both Phase B baseline and at least 1 postbaseline PANSS measurement.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 3); Week 15
    End point values
    		 AVP-786 Placebo
    Number of subjects analysed
    61
    54
    Units: score on a scale
        least squares mean (standard error)
    -0.3 ± 0.16
    -0.4 ± 0.16
    Statistical analysis title
    		 PGI-S Score
    Comparison groups
    AVP-786 v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59 [3]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.54
    Notes
    [3] - The MMRM analysis included fixed effects for treatment, trial centre, visit, treatment-by-visit interaction, and baseline-by-visit interaction. An unstructured covariance model was used.

    Secondary: Patient Global Impression of Change (PGI-C) Score

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    End point title
    		 Patient Global Impression of Change (PGI-C) Score
    End point description
    The PGI-C is a 7-point (1-7) subject-rated scale used to assess treatment response with respect to schizophrenia as follows: 1 = very much improved, = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, or 7 = very much worse. Missing PGI-C rating will not be imputed. mITT population included all subjects who were placebo run-in nonresponders, randomised in Phase B and in the safety population with both Phase B baseline and at least 1 postbaseline PANSS measurement.
    End point type
    Secondary
    End point timeframe
    At Weeks 6, 9, 12 and 15
    End point values
    		 AVP-786 Placebo
    Number of subjects analysed
    61
    54
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 6
    3.1 ± 1.07
    3.0 ± 1.05
        Week 9
    2.8 ± 1.10
    2.9 ± 0.98
        Week 12
    2.9 ± 1.15
    2.9 ± 1.05
        Week 15
    2.8 ± 1.20
    2.9 ± 1.00
    Statistical analysis title
    		 Comparison at Week 6
    Comparison groups
    AVP-786 v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6377 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.51
    Notes
    [4] - P-value and treatment difference (CI) were derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.
    Statistical analysis title
    		 Comparison at Week 9
    Comparison groups
    AVP-786 v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4827 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.24
    Notes
    [5] - P-value and treatment difference (CI) were derived from CMH row mean scores statistics controlling for study center.
    Statistical analysis title
    		 Comparison at Week 12
    Comparison groups
    AVP-786 v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8662 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 0.36
    Notes
    [6] - P-value and treatment difference (CI) were derived from CMH row mean scores statistics controlling for study center.
    Statistical analysis title
    		 Comparison at Week 15
    Comparison groups
    AVP-786 v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6062 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.3
    Notes
    [7] - P-value and treatment difference (CI) were derived from CMH row mean scores statistics controlling for study center.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of the study drug to end of follow up period (Up to Week 19)
    Adverse event reporting additional description
    Safety population included all subjects who were randomised in Phase B and took at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo (Run-in Period)
    Reporting group description
    		 Subjects received AVP-786 matching placebo capsules, orally, BID over a 3-week run-in period.

    Reporting group title
    AVP-786
    Reporting group description
    		 Subjects received AVP-786-28/4.9 (d6-DM 28 mg/Q 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, QD for 3 days followed by AVP-786-28/4.9 capsule, orally, BID for the next 4 days of titration period. Following the 1-week titration period, subjects received AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg), orally, BID for the remaining 11 weeks of the DBT period. 

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received AVP-786 matching placebo capsules, orally, BID over a 12-week DBT period.

    Serious adverse events
    		 Placebo (Run-in Period) AVP-786 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 65 (3.08%)
    0 / 60 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo (Run-in Period) AVP-786 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 136 (14.71%)
    25 / 65 (38.46%)
    14 / 60 (23.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 65 (3.08%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    General disorders and administration site conditions
    Decreased activity
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Ejaculation delayed
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Retrograde ejaculation
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    0
    Alcohol use disorder
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 136 (1.47%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    2
    1
    0
    Schizophrenia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Suspiciousness
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 65 (3.08%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Glucose urine present
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Urine protein/creatinine ratio abnormal
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 65 (3.08%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 65 (3.08%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Overdose
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Skin laceration
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Type V hyperlipidaemia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 136 (1.47%)
    2 / 65 (3.08%)
    1 / 60 (1.67%)
         occurrences all number
    2
    2
    1
    Extrapyramidal disorder
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    3 / 136 (2.21%)
    2 / 65 (3.08%)
    2 / 60 (3.33%)
         occurrences all number
    3
    2
    2
    Hyperresponsive to stimuli
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    2 / 136 (1.47%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    2
    0
    1
    Syncope
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Sedation
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    2 / 136 (1.47%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    2 / 136 (1.47%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    Toothache
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 65 (3.08%)
    1 / 60 (1.67%)
         occurrences all number
    0
    2
    1
    Back pain
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    0
    0
    2
    Bursitis
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bacterial vaginosis
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Corona virus infection
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Fungal infection
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 136 (0.74%)
    2 / 65 (3.08%)
    0 / 60 (0.00%)
         occurrences all number
    1
    2
    0
    Pharyngitis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 65 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Skin infection
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 65 (1.54%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Aug 2020
    The following changes were made as part of Amendment 1: 1. Increased number of sites. 2. Updated inclusion and exclusion criteria.
    27 May 2021
    The following changes were made as part of Amendment 2: 1. Increased number of sites to include European sites. 2. Expanded trial sites to include all of North America. 3. Updated estimated date of last subject completed. 4. Added secondary efficacy objective. 5. Updated inclusion and exclusion criteria.
    31 Mar 2022
    The following changes were made as per Amendment 3: 1. Updated sponsor information. 2. Updated inclusion and exclusion criteria.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 May 2023
    The study was terminated based on the Interim Analysis outcome and recommendation by the DMC, based on futility.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Not applicable
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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