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Clinical Trial Results:
A Phase 3, Multicenter, Long-term, Extension Study of the Safety and Efficacy of AVP-786 (deuterated [d6] dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the Treatment of Agitation in Patients with Dementia of the Alzheimer’s Type

Summary
EudraCT number	2017-002455-29
Trial protocol	HU ES FR PL BG CZ IT
Global end of trial date	05 Sep 2024

Results information
Results version number	v1(current)
This version publication date	23 Oct 2025
First version publication date	23 Oct 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

15-AVP-786-303

ISRCTN number

US NCT number

NCT02446132

WHO universal trial number (UTN)

Sponsor organisation name

Otsuka Pharmaceutical Development & Commercialization, Inc.

Sponsor organisation address

2440 Research Blvd, Rockville, MD, United States, 20850

Public contact

Clinical Transparency, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 8446878522, clinicaltransparency@otsuka-us.com

Scientific contact

Clinical Transparency, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 8446878522, clinicaltransparency@otsuka-us.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

05 Sep 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Sep 2024

Was the trial ended prematurely?

Main objective of the trial

The purpose of the study was to evaluate the long-term safety and maintenance of efficacy of AVP-786 for the treatment of agitation in subjects with dementia of the Alzheimer’s type.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Nov 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 1191

Worldwide total number of subjects

1191

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

109

From 65 to 84 years

950

85 years and over

132

Subject disposition

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Recruitment details

Subjects took part in the study at 217 clinical sites in the North America and Europe from 13 November 2015 to 06 September 2024.

Screening details

Of the 1197 subjects who were enrolled for the study, 1191 subjects received the study treatment, and 6 subjects did not receive the study drug. All eligible subjects received AVP-786-42.63/4.9, AVP-786-28/4.9, or AVP-786-18/4.9 depending on the last treatment received in the preceding study 15-AVP-786-301, 15-AVP-786-302, and 17-AVP-786-305.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

AVP-786 18 milligrams (mg)

Arm description

Subjects who received AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) capsules in the previous studies 15-AVP-786-301 (NCT02442765), 15-AVP-786-302 (NCT02442778), or 17-AVP-786-305 (NCT03393520) continued to receive AVP-786-18 (d6-DM 18 mg/Q 4.9 mg), capsules, twice a day for 52 weeks in the current study.

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

AVP-786-18 (d6-DM 18 mg/Q 4.9 mg) capsules were administered twice a day for 52-weeks.

AVP-786 28 mg

Arm description

Subjects who received AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) capsules in the previous studies 15-AVP-786-301 (NCT02442765), 15-AVP-786-302 (NCT02442778), or 17-AVP-786-305 (NCT03393520) continued to receive AVP-786-28 (d6-DM 28 mg/Q 4.9 mg), capsules, twice a day for 52 weeks in the current study.

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

AVP-786-28 (d6-DM 28 mg/Q 4.9 mg) capsules were administered twice a day for 52-weeks.

AVP-786 42.63 mg

Arm description

Subjects who received placebo in the previous studies 15-AVP-786-301 (NCT02442765), 15-AVP-786-302 (NCT02442778), or 17-AVP-786-305 (NCT03393520) and those who had delayed enrolment, started AVP-786-28/4.9 (d6-DM 28 mg/Q 4.9 mg) in the current study and were eventually titrated to receive AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg) capsules, twice a day for 52 weeks.

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

AVP-786-42.63 (d6-DM 42.63mg/Q 4.9 mg) capsules were administered twice a day for 52-weeks.

Number of subjects in period 1	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Started	166	516	509
Completed	109	332	324
Not completed	57	184	185
Adverse event, serious fatal	2	13	10
Physician decision	1	8	13
Consent withdrawn by subject	11	29	25
Trial Site Terminated by Sponsor	6	4	5
Adverse event, non-fatal	10	27	27
Non-compliance With Study Drug	2	2	3
Study Subject Withdrawal by Parent or Guardian	14	36	22
Study Terminated by Sponsor	4	35	58
Lost to follow-up	2	4	5
Reason not Specified	4	16	10
Lack of efficacy	1	10	6
Protocol deviation	-	-	1

Baseline characteristics

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Reporting group title

AVP-786 18 milligrams (mg)

Reporting group description

Reporting group title

AVP-786 28 mg

Reporting group description

Reporting group title

AVP-786 42.63 mg

Reporting group description

Reporting group values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg	Total
Number of subjects	166	516	509
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	74.1 ( 8.1 )	75.6 ( 7.9 )	75.0 ( 7.5 )	-
Gender categorical
Units: Subjects
Female	95	286	295	676
Male	71	230	214	515
Race
Units: Subjects
White	151	473	476	1100
Black or African American	13	29	24	66
Asian	2	4	2	8
American Indian or Alaska Native	0	1	0	1
Native Hawaiian or Other Pacific Islander	0	1	0	1
Other	0	4	2	6
Missing	0	4	5	9
Ethnicity
Units: Subjects
Hispanic or Latino	69	215	278	562
Not Hispanic or Latino	97	297	226	620
Missing	0	4	5	9

End points

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Reporting group title

AVP-786 18 milligrams (mg)

Reporting group description

Reporting group title

AVP-786 28 mg

Reporting group description

Reporting group title

AVP-786 42.63 mg

Reporting group description

Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) ^[1]

End point description

An adverse event (AE)is any untoward medical occurrence or unintended change (e.g. physical, psychological, or behavioral), including inter-current illness, whether considered related to treatment or not. An AE can therefore be any unfavorable and unintended sign (including any clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A TEAE is defined as an AE that occurred or worsened after the first dose of study treatment up until 30 days after last dose. Safety population included all subjects who received the study treatment.

End point type

Primary

End point timeframe

From first dose of study drug (in current study) up to 3 months after last dose of study drug (up to Week 64)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	166	516	509
Units: Subjects	109	304	292

No statistical analyses for this end point

Primary: Number of Subjects With Serious TEAE

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End point title

Number of Subjects With Serious TEAE ^[2]

End point description

A serious adverse event (SAE) is any AE occurring at any dose that results in death, life-threatening experience, persistent or significant disability/incapacity, in-patient hospitalization or prolongation of hospitalization or congenital anomaly/birth defect. A serious TEAE is defined as AE that occurred or worsened after the first dose of study treatment up until 30 days after last dose. Safety population included all subjects who received the study treatment.

End point type

Primary

End point timeframe

From first dose of study drug (in current study) up to 3 months after last dose of study drug (up to Week 64)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	166	516	509
Units: subjects	22	75	70

No statistical analyses for this end point

Primary: Number of Subjects With Potentially Clinically Significant Laboratory Test Abnormalities

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End point title

Number of Subjects With Potentially Clinically Significant Laboratory Test Abnormalities ^[3]

End point description

Laboratory assessments included clinical chemistry (alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon dioxide, cholesterol, creatinine kinase, creatinine, gamma glutamyl transferase, glucose, lactate dehydrogenase, magnesium, protein, potassium, sodium, triglycerides and uric acid), hematology (basophils, eosinophils/leukocytes, erythrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, lymphocytes/leukocytes, monocytes, monocytes/leukocytes, neutrophils/leukocytes, platelets). Number of subjects with clinically significant laboratory test abnormalities were reported as per criteria defined in statistical analysis plan (SAP). Safety population included all subjects who received the study treatment. Number of subjects analysed’ indicates the unique subjects who were evaluated for this outcome measure. ‘n’ indicates number of subjects evaluable for the specified category.

End point type

Primary

End point timeframe

Baseline (current study) up to 52 weeks

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	166	516	509
Units: subjects
Alanine aminotransferase: ≥3X ULN (n=164,510,508)	1	0	1
Albumin: ≤26 g/L (n=164,510,508)	3	1	2
Albumin (g/L): ≥60 g/L (n=164,510,508)	1	0	0
Alkaline Phosphatase: ≥3X ULN (n=164,510,508)	1	0	1
Aspartate Aminotransferase:≥3XULN (n=164,510,507)	2	0	0
Bilirubin: 5X ULN (n=164,510,508)	0	2	4
Blood Urea Nitrogen:≥10.71 mmol/L (n=158,450,398)	19	78	63
Calcium: ≤1.75 mmol/L (n=164,508,508)	0	1	0
Calcium: ≥3.0 mmol/L (n=164,508,508)	0	1	0
Carbon Dioxide: >40 mmol/L (n=164,510,508)	0	0	1
Cholesterol: ≥7.77 mmol/L (n=164,509,508)	7	19	18
Creatine Kinase: ≥3X ULN (n=164,507,505)	2	4	4
Creatinine: >132.6 umol/L (n=164,510,508)	8	53	26
Gamma Glutamyl Transferase:≥60U/L (n=164,501,488)	13	52	51
Glucose: ≤2.775 mmol/L (n=164,510,508)	3	9	4
Glucose: ≥11.1 mmol/L (n=164,510,508)	22	71	79
Lactate Dehydrogenase: ≥3X ULN (n=164,507,505)	0	1	2
Magnesium: <0.37 mmol/L (n=164,505,503)	1	1	0
Magnesium: >1.23 mmol/L (n=164,505,503)	0	0	1
Potassium: ≤3.0 mmol/L (n=164,510,507)	2	4	2
Potassium: ≥5.5 mmol/L (n=164,510,507)	6	32	34
Protein: ≤50 g/L (n=164,510,508)	3	0	4
Sodium: ≤130 mmol/L (n=164,510,508)	6	13	12
Sodium: ≥155 mmol/L (n=164,510,508)	0	1	2
Triglycerides: >3.39 mmol/L (n=164,508,508)	25	61	73
Uric Acid (Female): ≥505.58 umol/L (n=94,282,295)	3	22	14
Uric Acid (Male): ≥624.54 umol/L (n=70,226,213)	0	3	3
Basophils: >0.3 x10^9/L (n=164,510,507)	0	1	1
Eosinophils/Leukocytes: ≥10 % (n=164,509,505)	12	23	33
Erythrocytes: ≤2.5 x10^12/L (n=164,510,507)	0	0	1
Erythrocytes: ≥7.0 x10^12/L (n=164,510,507)	0	1	0
Hematocrit:<0.3 proportion of 1.0 (n=164,510,507)	4	7	9
Hematocrit:>0.5 proportion of 1.0 (n=164,510,507)	11	31	44
Hemoglobin: <100 g/L (n=164,510,507)	5	15	15
Hemoglobin: >180 g/L(n=164,510,507)	0	1	3
Leukocytes: ≤2.8 x10^9/L (n=164,510,507)	2	7	3
Leukocytes: ≥16 x10^9/L (n=164,510,507)	2	4	5
Lymphocytes: ≤0.5 x10^9/L (n=164,510,507)	0	4	7
Lymphocytes: >4 x10^9/L (n=164,510,507)	1	8	6
Lymphocytes/Leukocytes: ≤10 % (n=164,509,505)	6	30	21
Lymphocytes/Leukocytes: ≥60 % (n=164,509,505)	0	4	6
Monocytes (10^9/L): >1 x10^9/L (n=164,510,507)	7	27	23
Monocytes/Leukocytes: ≥15 % (n=164,509,505)	5	24	23
Neutrophils/Leukocytes: ≤15 % (n=164,509,505)	0	1	1
Platelets: ≤100 x10^9/L (n=164,510,507)	2	4	6
Platelets: ≥700 x10^9/L (n=164,510,507)	0	0	1

No statistical analyses for this end point

Primary: Number of Subjects With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Abnormalities

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End point title

Number of Subjects With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Abnormalities ^[4]

End point description

A resting 12-lead ECG was performed for all the subjects. ECG data included PR interval (milliseconds {msec} ) and QTcF (msec) along with change from baseline (CFB) in QTcF. Number of subjects with potentially clinically significant ECG abnormalities was reported as per the criteria defined in SAP. Safety population included all subjects who received the study treatment. 'Number of subjects analysed’ indicates the unique subjects who were evaluated for this outcome measure. ‘n’ indicates number of subjects evaluable for the specified category.

End point type

Primary

End point timeframe

Baseline (current study) up to 52 weeks

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	166	516	509
Units: subjects
PR Interval males,females:>200-≤22(n=162,503,192)	21	66	60
PR Interval males,females:>220-≤25(n=162,503,192)	13	33	28
PR Interval males,females:>250msec(n=162,503,192)	5	13	9
QTcF (males):>450 to ≤480 msec (n=68,222,207)	9	28	23
QTcF (males): >480 to ≤500 msec (n=68,222,207)	2	2	1
QTcF (females):>470 to ≤485 msec (n=94, 282, 292)	3	12	10
QTcF (females):>485 to ≤500 msec (n=94, 282, 292)	0	4	2
QTcF (females): >500 msec (n=94, 282, 292)	0	1	1
QTcF CFB (male and females):≥30 (n=162, 504, 499)	18	64	66
QTcF CFB (male and females):≥60 (n=162, 504, 499)	1	5	5

No statistical analyses for this end point

Primary: Number of Subjects With Any Abnormal, Clinically Significant Physical and Neurological Examination Finding

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End point title

Number of Subjects With Any Abnormal, Clinically Significant Physical and Neurological Examination Finding ^[5]

End point description

The physical examination included assessments of head, eyes, ears, nose, throat, lymph nodes, skin, extremities, respiratory, gastrointestinal, musculoskeletal, cardiovascular, and nervous systems. The neurological examination included assessments of mental status, cranial nerves, motor system, reflexes, coordination, gait and station, and sensory system. Safety population included all subects who received the study treatment.

End point type

Primary

End point timeframe

Baseline, Week 52

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	166	516	509
Units: subjects	2	4	4

No statistical analyses for this end point

Primary: Number of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs

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End point title

Number of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs ^[6]

End point description

Vital signs measurements included systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). Blood pressure (i.e., SBP, DBP) and heart rate were measured in the supine and standing positions after the subject had been in each position for at least 5 and 3 minutes, respectively. Number of subjects with clinically significant vital sign abnormalities were reported as per criteria defined in SAP. The categories with at least one subject with clinically significant vital signs abnormalities are reported here. Safety population included all subjects who received the study treatment. 'Number of subjects analysed’ indicates the unique subjects who were evaluated for this outcome measure. ‘n’ indicates number of subjects evaluable for the specified category.

End point type

Primary

End point timeframe

Baseline (current study) up to 52 weeks

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	166	516	509
Units: subjects
SBP:≤90&≥20 decrease from baseline(n=164,507,509)	5	18	14
SBP:>180&≥20increase from baseline(n=164,507,509)	0	6	4
DBP:≤50&≥15decrease from baseline (n=164,507,509)	4	8	8
DBP:≥105&≥15increase from baseline(n=164,507,509)	2	3	8
HR:≤50&≥15decrease from baseline (n=164,507,509)	0	7	7
HR:≥120&≥15increase from baseline (n=164,507,509)	0	4	1
SBP≥10&HR≥5increase from baseline (n=164,507,509)	53	147	155
DBP≥5&HR≥5increase from baseline (n=164,507,509)	61	239	225

No statistical analyses for this end point

Primary: Change From Baseline in the Sheehan Suicidality Tracking Scale (S-STS) Score at Week 64

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End point title

Change From Baseline in the Sheehan Suicidality Tracking Scale (S-STS) Score at Week 64 ^[7]

End point description

The S-STS is a prospective scale that assesses treatment-emergent suicidal thoughts and behaviors. Each item of the S-STS is scored on a 5-point Likert scale as: 0 = Not at all, 1 = A little, 2 = Moderate, 3 = Very, 4 = Extremely. Higher scores indicate greater severity of suicidal ideation and/or behavior. A negative change from baseline reflects a reduction in suicidal thoughts or behaviors over time. Safety population included all subjects who received the study treatment. ‘Subjects analysed’ indicates the number of subjects evaluable for the outcome measure at the specified time point.

End point type

Primary

End point timeframe

Baseline (current study), Week 64

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	92	276	304
Units: score on a scale
arithmetic mean (standard deviation)
Total Score	-0.0 ( 0.1 )	0.0 ( 0.1 )	-0.0 ( 0.1 )

No statistical analyses for this end point

Primary: Change From Baseline in the Mini-Mental State Examination (MMSE) Score at Week 52

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End point title

Change From Baseline in the Mini-Mental State Examination (MMSE) Score at Week 52 ^[8]

End point description

The MMSE is a brief questionnaire that is used to assess cognitive impairment and severity of cognitive impairment. The MMSE scale comprises 11 questions or simple tasks concerning orientation, memory, attention, and language to evaluate a subject's cognitive state and are scored as follows: Orientation to Time - 0 to 5; Orientation to Place - 0 to 5; Registration - 0 to 3; Attention and Calculation - 0 to 5; Recall - 0 to 3; Naming - 0 to 2; Repetition - 0 to 1; Comprehension - 0 to 3; Reading - 0 to 1; Writing - 0 to 1; Drawing - 0 to 1. The total score was calculated by summing all of the item scores and ranges from 0 to 30. Higher scores indicate milder cognitive impairment. Negative change from baseline indicates decline in cognitive performance. Safety population included all subjects who received the study treatment. ‘Subjects analysed’ indicates the number of subjects evaluable for the outcome measure at the specified time point.

End point type

Primary

End point timeframe

Baseline (current study), Week 52

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	121	372	366
Units: score on a scale
arithmetic mean (standard deviation)	-0.8 ( 4.6 )	-0.7 ( 4.9 )	-0.1 ( 4.1 )

No statistical analyses for this end point

Primary: Change From Baseline in the Epworth Sleepiness Scale (ESS) Score at Week 52

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End point title

Change From Baseline in the Epworth Sleepiness Scale (ESS) Score at Week 52 ^[9]

End point description

The ESS is an 8-item questionnaire that is used to measure sleepiness by rating the probability of falling asleep on 8 different situations that most people engage in during the day. The 8 questions are rated on a 4-point scale (0 to 3) where 0 = would never doze, 1 = slight chance of dozing, 2 = moderate chance of dozing, and 3 = high chance of dozing. The scores are summed to give an overall score of 0 to 24 . A total score of 0 to 9 is considered to be normal. Higher score indicates greater daytime sleepiness. Negative change from baseline indicate improvement in daytime sleepiness. Safety population included all subjects who received the study treatment. ‘Subjects analysed’ indicates the number of subjects evaluable for the outcome measure at the specified time point.

End point type

Primary

End point timeframe

Baseline (current study), Week 52

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypotheses were tested for the primary end point.

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	83	297	338
Units: score on a scale
arithmetic mean (standard deviation)	-0.01 ( 4.43 )	0.07 ( 4.39 )	0.50 ( 3.93 )

No statistical analyses for this end point

Secondary: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score at Week 64

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End point title

Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score at Week 64

End point description

The CMAI is used to assess the frequency of manifestations of agitated behaviors in elderly persons. It consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. These distinct agitation syndromes include aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior. Each of the 29 items is rated on a 7-point scale of frequency (1 = never, 2 = less than once a week but still occurring, 3 = once or twice a week, 4 = several times a week, 5 = once or twice a day, 6 = several times a day, 7 = several times an hour). The ratings are based on the 2 weeks preceding assessment of the CMAI. Higher scores indicate higher frequency of agitated behaviours while lower scores indicate lower frequency of agitated behaviours.

End point type

Secondary

End point timeframe

Baseline (current study), Week 64

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	0 ^[10]	0 ^[11]	0 ^[12]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[10] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[11] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[12] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.

No statistical analyses for this end point

Secondary: Change From Baseline in the Agitation/Aggression, Irritability/Lability, and Aberrant Motor Behavior Domain Scores of the Neuropsychiatric Inventory (NPI) at Week 52

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End point title

Change From Baseline in the Agitation/Aggression, Irritability/Lability, and Aberrant Motor Behavior Domain Scores of the Neuropsychiatric Inventory (NPI) at Week 52

End point description

The NPI is a validated clinical instrument used to assess neuropsychiatric symptoms. It evaluates 12 neuropsychiatric symptom domains including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep and nighttime behavioral disorders, and appetite/eating disorders. Each symptom domain is rated by the caregiver based on the frequency (1 to 4) and severity (1 to 3) of symptoms, and a composite domain score is calculated by multiplying frequency and severity (range: 1–12). Additionally, caregiver distress for each positive symptom domain is rated on a 6-point scale (0 = not at all distressing, 5 = extremely distressing). In this study, the three NPI domains assessed were agitation/aggression, irritability/lability, and aberrant motor behavior. Higher scores indicate greater severity and frequency of neuropsychiatric symptoms.

End point type

Secondary

End point timeframe

Baseline (current study), Week 52

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	0 ^[13]	0 ^[14]	0 ^[15]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[13] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[14] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[15] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.

No statistical analyses for this end point

Secondary: Change From Baseline in the Modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change-Agitation (mADCS-CGIC-Agitation) Score at Week 64

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End point title

Change From Baseline in the Modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change-Agitation (mADCS-CGIC-Agitation) Score at Week 64

End point description

The mADCS-CGIC-Agitation is used to assess agitation in individuals with Alzheimer’s disease. It includes questions focused on agitation and uses a semi-structured interview format involving both the subject and their caregiver. The clinician rates the subject’s overall clinical status using a 7-point scale: 1 = marked improvement, 2 = moderate improvement, 3 = minimal improvement, 4 = no change, 5 = minimal worsening, 6 = moderate worsening, and 7 = marked worsening. Lower scores indicate improvement in agitation symptoms, while higher scores indicate worsening.

End point type

Secondary

End point timeframe

Baseline (current study), Week 64

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	0 ^[16]	0 ^[17]	0 ^[18]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[16] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[17] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[18] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.

No statistical analyses for this end point

Secondary: Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score at Week 52

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End point title

Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score at Week 52

End point description

The CGIS is an observer-rated scale that measures illness severity. The CGIS-Agitation is a 7-point (1-7) scale (1 = normal, not at all ill; 7 = extremely ill) that assessed the severity of agitation in this study. Higher scores indicate severe agitation, while the lower scores indicate little or no agitation.

End point type

Secondary

End point timeframe

Baseline (current study), Week 52

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	0 ^[19]	0 ^[20]	0 ^[21]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[19] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[20] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[21] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.

No statistical analyses for this end point

Secondary: Change From Baseline in the Patient Global Impression of Change (PGIC) Score at Week 52

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End point title

Change From Baseline in the Patient Global Impression of Change (PGIC) Score at Week 52

End point description

The PGIC is a 7-point scale used to assess perceived treatment response, as evaluated by the subject's caregiver. The caregiver rates the overall change in the subject's condition since the start of treatment. The PGIC score ranges from 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Lower scores reflect greater improvement, while higher scores indicate worsening of the sucondition.

End point type

Secondary

End point timeframe

Baseline (current study), Week 52

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	0 ^[22]	0 ^[23]	0 ^[24]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[22] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[23] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[24] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.

No statistical analyses for this end point

Secondary: Change From Baseline in the Dementia Quality of Life (DEMQOL) Score at Week 52

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End point title

Change From Baseline in the Dementia Quality of Life (DEMQOL) Score at Week 52

End point description

The DEMQOL is a validated scale used to assess health-related quality of life in individuals with dementia and their caregivers. It includes two versions: a 28-item version completed by the subject (DEMQOL), and a 31-item proxy version completed by the caregiver (DEMQOL-proxy). Each item is rated using a 4-point scale to reflect the frequency or severity of health-related concerns: 1 = A lot, 2 = Quite a bit, 3 = A little, 4 = Not at all. Total score is derived by sum of all item scores, excluding item 29 of DEMQOL and item 32 of DEMQOL-proxy. Lower scores indicate better quality of life.

End point type

Secondary

End point timeframe

Baseline (current study), Week 52

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	0 ^[25]	0 ^[26]	0 ^[27]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[25] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[26] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[27] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.

No statistical analyses for this end point

Secondary: Change From Baseline in the Resource Utilization in Dementia (RUD) Score at Week 52

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End point title

Change From Baseline in the Resource Utilization in Dementia (RUD) Score at Week 52

End point description

The RUD is a standardized tool used to estimate healthcare costs associated with dementia. It assesses the use of both formal and informal (e.g., hospitalizations, doctor visits, living assistance, and unprofessional caregiver time) healthcare resources. The instrument is administered as a semi-structured interview with the subject's primary caregiver. It consists of two main sections: one evaluates the caregiver’s burden, including lost work and leisure time, and the other documents the subjetc's use of healthcare services. Total healthcare costs are calculated by multiplying the quantity of resources used (e.g., number of doctor visits, hours of caregiver, nights in accommodation) by unit costs. Higher estimated totals reflect greater economic impact associated with dementia care.

End point type

Secondary

End point timeframe

Baseline (current study), Week 52

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	0 ^[28]	0 ^[29]	0 ^[30]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[28] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[29] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[30] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.

No statistical analyses for this end point

Secondary: Change From Baseline in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) for Subjects From Study 17-AVP-786-305 at Week 52

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End point title

Change From Baseline in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) for Subjects From Study 17-AVP-786-305 at Week 52

End point description

The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life. It consists of two components: a descriptive system and the EuroQol Visual Analogue Scale (EQ VAS). The descriptive system covers five health dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 5-level scale: 1 = No problems, 2 = Slight problems, 3 = Moderate problems, 4 = Severe problems, 5 = Extreme problems. The EQ VAS component allows subjects or caregivers to rate the individual’s overall health on a vertical scale from 0 (the worst imaginable health state) to 100 (the best imaginable health state). Only subjects from Study 17-AVP-786-305 with a MMSE score of 10 or higher at the baseline visit were planned to complete the subject-rated version.

End point type

Secondary

End point timeframe

Baseline (current study), Week 52

End point values	AVP-786 18 milligrams (mg)	AVP-786 28 mg	AVP-786 42.63 mg
Number of subjects analysed	0 ^[31]	0 ^[32]	0 ^[33]
Units: score on a scale
arithmetic mean (standard deviation)	( )	( )	( )

Notes
[31] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[32] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.
[33] - As AVP-786 development discontinued, no efficacy data was collected, only safety data was analysed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug (in current study) up to 3 months after last dose of study drug (up to Week 64)

Adverse event reporting additional description

Safety population included all subjects who received the study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

AVP-786-18

Reporting group description

Reporting group title

AVP-786-42.63

Reporting group description

Reporting group title

AVP-786-28

Reporting group description

Serious adverse events	AVP-786-18	AVP-786-42.63	AVP-786-28
Total subjects affected by serious adverse events
subjects affected / exposed	22 / 166 (13.25%)	70 / 509 (13.75%)	75 / 516 (14.53%)
number of deaths (all causes)	4	16	22
number of deaths resulting from adverse events	2	11	17
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Follicular thyroid cancer
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Lung cancer metastatic
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Transitional cell carcinoma
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Myelodysplastic syndrome
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Renal cancer
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Vascular disorders
Hypertension
subjects affected / exposed	1 / 166 (0.60%)	2 / 509 (0.39%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral embolism
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Femoral artery aneurysm
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Orthostatic hypotension
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery aneurysm
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 2
Asthenia
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Disease progression
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Inflammation
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Prostatitis
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Acute respiratory failure
subjects affected / exposed	1 / 166 (0.60%)	2 / 509 (0.39%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Pneumothorax
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis aspiration
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 166 (0.00%)	2 / 509 (0.39%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Hypoxia
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Pulmonary oedema
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Psychiatric disorders
Aggression
subjects affected / exposed	1 / 166 (0.60%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Agitation
subjects affected / exposed	4 / 166 (2.41%)	4 / 509 (0.79%)	6 / 516 (1.16%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 166 (0.00%)	4 / 509 (0.79%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disturbance in social behaviour
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphemia
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Suicidal ideation
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
QRS axis abnormal
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Blood osmolarity increased
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood glucose increased
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Injury, poisoning and procedural complications
Craniocerebral injury
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 166 (0.00%)	2 / 509 (0.39%)	4 / 516 (0.78%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Femur fracture
subjects affected / exposed	0 / 166 (0.00%)	3 / 509 (0.59%)	3 / 516 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	2 / 166 (1.20%)	5 / 509 (0.98%)	12 / 516 (2.33%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Incisional hernia
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Lumbar vertebral fracture
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Ligament rupture
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Intentional medical device removal by patient
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 166 (0.00%)	2 / 509 (0.39%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Spinal fracture
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheostomy malfunction
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Rib fracture
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Skin laceration
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Wound dehiscence
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Cardiac disorders
Atrioventricular block first degree
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Acute myocardial infarction
subjects affected / exposed	0 / 166 (0.00%)	2 / 509 (0.39%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Bundle branch block right
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Bundle branch block left
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cardiac failure congestive
subjects affected / exposed	1 / 166 (0.60%)	2 / 509 (0.39%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cardio-respiratory arrest
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Cardiopulmonary failure
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Coronary artery disease
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Sinus bradycardia
subjects affected / exposed	0 / 166 (0.00%)	2 / 509 (0.39%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary valve stenosis
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Nervous system disorders
Basal ganglia haematoma
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Balance disorder
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain hypoxia
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Depressed level of consciousness
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Cerebral haemorrhage
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Dementia Alzheimer's type
subjects affected / exposed	1 / 166 (0.60%)	1 / 509 (0.20%)	3 / 516 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1
Dementia
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 166 (0.00%)	2 / 509 (0.39%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Dysstasia
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Neurodegenerative disorder
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Metabolic encephalopathy
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Guillain-Barre syndrome
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 166 (1.81%)	4 / 509 (0.79%)	4 / 516 (0.78%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Unresponsive to stimuli
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 166 (0.00%)	2 / 509 (0.39%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Normocytic anaemia
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Leukocytosis
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Thrombocytosis
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Eye disorders
Keratitis
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Small intestinal obstruction
subjects affected / exposed	0 / 166 (0.00%)	2 / 509 (0.39%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Volvulus of small bowel
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Gastric ulcer
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Dysphagia
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Melaena
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	3 / 516 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Cholecystitis acute
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Skin and subcutaneous tissue disorders
Dermatitis contact
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Azotaemia
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Acute kidney injury
subjects affected / exposed	1 / 166 (0.60%)	1 / 509 (0.20%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 166 (0.00%)	4 / 509 (0.79%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neurogenic bladder
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Musculoskeletal and connective tissue disorders
Myositis
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Musculoskeletal stiffness
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Bacteraemia
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colonic abscess
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Cellulitis
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
COVID-19
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Lower respiratory tract infection
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	2 / 516 (0.39%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pneumonia viral
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Psoas abscess
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Gastroenteritis viral
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 166 (0.60%)	2 / 509 (0.39%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyuria
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 166 (1.20%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection viral
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Necrotising fasciitis
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 166 (0.60%)	8 / 509 (1.57%)	3 / 516 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 9	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 166 (1.81%)	7 / 509 (1.38%)	5 / 516 (0.97%)
occurrences causally related to treatment / all	0 / 3	0 / 9	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Wound infection
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	5 / 516 (0.97%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Hyponatraemia
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 166 (0.00%)	1 / 509 (0.20%)	0 / 516 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Lactic acidosis
subjects affected / exposed	0 / 166 (0.00%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 166 (0.60%)	0 / 509 (0.00%)	1 / 516 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	AVP-786-18	AVP-786-42.63	AVP-786-28
Total subjects affected by non serious adverse events
subjects affected / exposed	54 / 166 (32.53%)	149 / 509 (29.27%)	150 / 516 (29.07%)
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	10 / 166 (6.02%)	11 / 509 (2.16%)	16 / 516 (3.10%)
occurrences all number	11	17	23
Fall
subjects affected / exposed	27 / 166 (16.27%)	60 / 509 (11.79%)	79 / 516 (15.31%)
occurrences all number	50	99	181
Nervous system disorders
Headache
subjects affected / exposed	10 / 166 (6.02%)	17 / 509 (3.34%)	14 / 516 (2.71%)
occurrences all number	11	20	16
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	10 / 166 (6.02%)	26 / 509 (5.11%)	28 / 516 (5.43%)
occurrences all number	12	32	31
Psychiatric disorders
Agitation
subjects affected / exposed	10 / 166 (6.02%)	39 / 509 (7.66%)	32 / 516 (6.20%)
occurrences all number	15	56	85
Infections and infestations
Urinary tract infection
subjects affected / exposed	13 / 166 (7.83%)	43 / 509 (8.45%)	45 / 516 (8.72%)
occurrences all number	19	56	61

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Were there any global substantial amendments to the protocol? Yes

01 Jul 2015

Revised footnotes to specify that the EQ‑5D‑5L, DEMQOL, and ADAS‑Cog assessments were to be performed only for subjects with an MMSE score of ≥10 at baseline, rather than at the visit. A new footnote required thyroid function tests (TSH, and reflex T3 and T4 if TSH was abnormal) at the baseline visit for subjects from Study 12‑AVR‑131. An exclusion criterion was added for subjects with a serious risk of suicide based on the S‑STS. Clarified that study medication was to be administered by a caregiver, family member, nursing staff, or self‑administered under supervision, with dosing times recorded in a diary. Reporting requirements specified that any death during the study or within 30 days after treatment discontinuation had to be reported to the sponsor. Laboratory updates included adding leucocyte esterase and nitrates to urinalysis and reiterating baseline thyroid function testing for eligible subjects . For suicidality monitoring, any change in S‑STS score indicating suicidality had to be evaluated and reported. Clarified that DEMQOL was a 28‑item questionnaire for subjects with MMSE ≥10 at baseline and that the EQ‑5D‑5L subject version applied only to subjects meeting this baseline MMSE criterion.

01 Oct 2015

The CMAI was added as a new efficacy measure, and the CGIC assessment was separated into Overall Clinical Status (ADCS‑CGIC‑Overall) and agitation syndrome (mADCS‑CGIC‑Agitation). The EQ‑5D‑5L scale was removed from all assessments. For subjects from study 12‑AVR‑131, a screening period of up to four weeks was introduced, and the number of scheduled visits was updated to up to nine. The Schedule of Evaluations and Visits was revised, separating tables for Study 12‑AVR‑131 from those for studies 15‑AVP‑786‑301 and 302, adding a screening visit for the former, introducing CMAI assessments at specific visits, and deleting certain measures such as ZBI, PGIC, mADCS‑CGIC‑Agitation, CGIS, NPI, EQ‑5D‑5L, and MMSE at Visit 7. Deleted the ZBI at Visits 4 and 6 and EQ-5D-5L at all visits. Inclusion criterion 6 and 9 and exclusion criteria 5 and 7 were updated. Specified that dose can be adjusted after Day 22 at any time during the study. Several scales, including NPI, CGIS Agitation, ADCS CGIC Overall, mADCS CGIC Agitation, ZBI, PGIC, CSDD, and GMHR, had revised schedules, scoring clarifications, or visit changes. Efficacy analyses were updated to reflect the addition of CMAI, the separation of CGIC assessments, and the removal of EQ5D5L.

16 May 2016

Refined the dosing regimen for subjects on placebo in preceding studies and those from Study 12‑AVR‑131. The number of clinic visits increased from up to nine to up to thirteen. Additional assessments such as vital signs, S‑STS, ESS, drug administration in clinic, and medication/diary review were added. The Epworth Sleepiness Scale (ESS) was added as a safety measure, and the Alzheimer’s Disease Cooperative Study‑Activities of Daily Living Inventory (ADCS‑ADL) replaced the IADL as an efficacy measure. Inclusion and exclusion criteria were updated, which includes lowering the upper age limit to 90 for certain subjects , adjusting MMSE score requirements, extending stable‑dose requirements, and clarifying the handling of PVCs. ECG requirements were updated for calculating QTcF changes based on prior‑study or baseline measurements. Concomitant medication rules were revised to allow initiation or adjustment of Alzheimer’s disease treatments during the study. Safety procedures were expanded to include orthostatic vital signs, clarified physical/neurological exam elements, revised laboratory and pregnancy testing schedules, and specified ECG timing. The CMAI long‑form was confirmed for use, and additional caregiver input collected at Visit 4. The visit schedule and order of procedures were updated, and safety analysis plans were updated to incorporate ESS and report laboratory parameter shifts from baseline to end of treatment. Replaced the IADL with the ADCS-ADL

28 Feb 2017

Revised the planned enrollment to approximately 700 subjects at about 135 centers and updated the study duration to approximately 56 weeks, extending to about 64 weeks for around 100 subjects who had a follow‑up visit three months after their last dose. Added AVP-786-42.63/4.9 dose. Safety procedures were clarified to include vital signs at all visits except Follow‑up Visits and to specify that the Epworth Sleepiness Scale (ESS) would only be administered to subjects with an MMSE score of ≥10 at baseline. Efficacy assessments were expanded to include CMAI and mADCS‑CGIC at Follow‑up Visits, with mADCS‑CGIC measuring change from the last treatment visit (Visit 8/ET). The description of the ADCS‑ADL was clarified. Study procedures were updated to align with the revised schedule, adding in‑clinic follow‑up visits and removing the prior 30‑day post‑treatment follow‑up phone call. The analysis population description was updated to reflect reporting by all four treatment groups, including the newly added AVP‑786‑42.63/4.9 arm.

23 Oct 2017

Increased the planned enrollment to approximately 1,000 subjects at about 250 centers globally and expanded eligibility to include subjects who successfully completed Study 17‑AVP‑786‑305 and were not participating in another study. The amendment clarified that the study was an extension trial also including subjects from Study 17‑AVP‑786‑305. For subjects who had received placebo in preceding studies and subjects from Study 12‑AVR‑131, treatment began with AVP‑786‑28/4.9 once daily for the first seven days, then twice daily for the next 14 days, and from Day 22 onward transitioned to AVP‑786‑42.63/4.9 twice daily unless adjusted after Day 22. Safety and tolerability measures were updated, removing ADAS‑cog and TUG test, while efficacy assessments were updated to NPI, and EQ‑5D‑5L added for subjects from Study 17‑AVP‑786‑305. Several assessments including ADCS‑CGIC, ZBI, CSDD, GMHR, and ADCS‑ADL were removed. Inclusion and exclusion criteria were revised to reflect the expanded population and clarified dose adjustment allowances for all subjects . Safety procedures were updated, including the removal of the “30‑day AE follow‑up after last dose” rule due to the addition of an in‑clinic follow‑up visit at that timepoint. The MMSE baseline was defined based on the preceding study, and several ESS visits were removed. Efficacy schedules for mADCS‑CGIC Agitation, NPI, and CMAI were revised, with the CMAI caregiver questionnaire removed.

01 Feb 2021

The itemized changes to procedures in the protocol described for each section are intended to decrease the study burden for subjects and their caregivers. To support this objective, as the analysis requirements will be met with the currently enrolled population, the mADCS-CGIC Agitation, RUD, and DEMQOL will no longer be administered following the implementation of Protocol Amendment 6. The amendment includes clarifications throughout the document where the population is described to state that subjects with Medical Monitor prior approval may delay enrollment into Study 15-AVP-786-303 but will be required to meet all screening and eligibility requirements prior to enrollment. As this is applied to more than Study 12-AVR-131, the wording has been simplified in the text to references to subjects who delay enrollment. Clarified throughout the document that pregnancy testing is to be conducted for “subjects ” of childbearing potential. The appendices including samples of the study scales (as these are included in the Study Procedures Manual) and Declaration of Helsinki were removed. References were updated to align with changes in the text.

26 Jan 2022

The protocol was updated to reflect the change in sponsor from Avanir Pharmaceuticals, Inc. to Otsuka Pharmaceutical Development & Commercialization, Inc.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The study was prematurely terminated due to discontinuation of development of the AVP-786 compound.

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Clinical trials

Clinical Trial Results: A Phase 3, Multicenter, Long-term, Extension Study of the Safety and Efficacy of AVP-786 (deuterated [d6] dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the Treatment of Agitation in Patients with Dementia of the Alzheimer’s Type

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

Primary: Number of Subjects With Serious TEAE

Primary: Number of Subjects With Serious TEAE

Primary: Number of Subjects With Potentially Clinically Significant Laboratory Test Abnormalities

Primary: Number of Subjects With Potentially Clinically Significant Laboratory Test Abnormalities

Primary: Number of Subjects With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Abnormalities

Primary: Number of Subjects With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Abnormalities

Primary: Number of Subjects With Any Abnormal, Clinically Significant Physical and Neurological Examination Finding

Primary: Number of Subjects With Any Abnormal, Clinically Significant Physical and Neurological Examination Finding

Primary: Number of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs

Primary: Number of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs

Primary: Change From Baseline in the Sheehan Suicidality Tracking Scale (S-STS) Score at Week 64

Primary: Change From Baseline in the Sheehan Suicidality Tracking Scale (S-STS) Score at Week 64

Primary: Change From Baseline in the Mini-Mental State Examination (MMSE) Score at Week 52

Primary: Change From Baseline in the Mini-Mental State Examination (MMSE) Score at Week 52

Primary: Change From Baseline in the Epworth Sleepiness Scale (ESS) Score at Week 52

Primary: Change From Baseline in the Epworth Sleepiness Scale (ESS) Score at Week 52

Secondary: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score at Week 64

Secondary: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Composite Score at Week 64

Secondary: Change From Baseline in the Agitation/Aggression, Irritability/Lability, and Aberrant Motor Behavior Domain Scores of the Neuropsychiatric Inventory (NPI) at Week 52

Secondary: Change From Baseline in the Agitation/Aggression, Irritability/Lability, and Aberrant Motor Behavior Domain Scores of the Neuropsychiatric Inventory (NPI) at Week 52

Secondary: Change From Baseline in the Modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change-Agitation (mADCS-CGIC-Agitation) Score at Week 64

Secondary: Change From Baseline in the Modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change-Agitation (mADCS-CGIC-Agitation) Score at Week 64

Secondary: Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score at Week 52

Secondary: Change From Baseline in the Clinical Global Impression of Severity of Illness (CGIS)-Agitation Domain Score at Week 52

Secondary: Change From Baseline in the Patient Global Impression of Change (PGIC) Score at Week 52

Secondary: Change From Baseline in the Patient Global Impression of Change (PGIC) Score at Week 52

Secondary: Change From Baseline in the Dementia Quality of Life (DEMQOL) Score at Week 52

Secondary: Change From Baseline in the Dementia Quality of Life (DEMQOL) Score at Week 52

Secondary: Change From Baseline in the Resource Utilization in Dementia (RUD) Score at Week 52

Secondary: Change From Baseline in the Resource Utilization in Dementia (RUD) Score at Week 52

Secondary: Change From Baseline in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) for Subjects From Study 17-AVP-786-305 at Week 52

Secondary: Change From Baseline in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) for Subjects From Study 17-AVP-786-305 at Week 52

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 3, Multicenter, Long-term, Extension Study of the Safety and Efficacy of AVP-786 (deuterated [d6] dextromethorphan hydrobromide [d6-DM]/quinidine sulfate [Q]) for the Treatment of Agitation in Patients with Dementia of the Alzheimer’s Type