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Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of ALKS 9072 in Subjects with Acute Exacerbation of Schizophrenia

Summary
EudraCT number	2012-003445-15
Trial protocol	BG
Global end of trial date	11 Mar 2014

Results information
Results version number	v1(current)
This version publication date	14 Aug 2016
First version publication date	14 Aug 2016
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

ALK9072-003

ISRCTN number

-

US NCT number

NCT01469039

WHO universal trial number (UTN)

-

Sponsor organisation name

Alkermes

Sponsor organisation address

852 Winter Street, Waltham, United States, 02451

Public contact

ARISTADA Medical Information, Alkermes, Inc., 01 866-274-7823, usmedinfo@alkermes.com

Scientific contact

ARISTADA Medical Information, Alkermes, Inc., 01 866-274-7823, usmedinfo@alkermes.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

03 Jul 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Jan 2014

Global end of trial reached?

Yes

Global end of trial date

11 Mar 2014

Was the trial ended prematurely?

No

Main objective of the trial

The study will determine the efficacy of ALKS 9072 (also known as aripiprazole lauroxil or ALKS 9070) for the treatment of schizophrenia in subjects experiencing an acute exacerbation.

Protection of trial subjects

Subjects were monitored in an inpatient setting for at least 2 weeks after administration of the 1st dose of intramuscular (IM) study drug. Subjects were discharged from the inpatient facility when assessed as clinically stable and appropriate for discharge as determined by the study investigator. For subjects who had never taken aripiprazole, a test dose of oral aripiprazole 5 mg was administered by mouth daily for 2 days prior to randomization, in order to assess individual tolerability prior to proceeding to injectable study drug.

Background therapy

Currently prescribed antipsychotics were required to be discontinued during screening and prior to administration of study drug.

Evidence for comparator

-

Actual start date of recruitment

15 Dec 2011

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 59

Country: Number of subjects enrolled

Malaysia: 24

Country: Number of subjects enrolled

Philippines: 53

Country: Number of subjects enrolled

Romania: 17

Country: Number of subjects enrolled

Russian Federation: 73

Country: Number of subjects enrolled

Ukraine: 90

Country: Number of subjects enrolled

United States: 307

Worldwide total number of subjects

623

EEA total number of subjects

76

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

621

From 65 to 84 years

2

85 years and over

0

Subject disposition

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Recruitment details

Included subjects with schizophrenia experiencing an acute exacerbation episode.

Screening details

Subjects were admitted to an inpatient study unit. Currently prescribed antipsychotics were discontinued prior to administration of study drug. One randomized subject was discontinued for a protocol violation prior to receiving investigational treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

All IM injections were administered under double-blind conditions. An unblinded pharmacist prepared investigational product for IM administration. The unblinded pharmacist provided the IM study drug (in a syringe) to an identified blinded qualified staff member (injector) for administration.

Are arms mutually exclusive

Yes

aripiprazole lauroxil 441 mg

Arm description

-

Arm type

Experimental

Investigational medicinal product name

aripiprazole lauroxil

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

441 mg IM injection, given monthly

aripiprazole lauroxil 882 mg

Arm description

-

Arm type

Experimental

Investigational medicinal product name

aripiprazole lauroxil

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

881 mg IM injection, given monthly

AL Placebo

Arm description

aripiprazole lauroxil-matched placebo

Arm type

Placebo

Investigational medicinal product name

Matched Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Emulsion for injection/infusion

Routes of administration

Intramuscular use

Dosage and administration details

Volume-matched to aripiprazole lauroxil doses, given monthly

Number of subjects in period 1	aripiprazole lauroxil 441 mg	aripiprazole lauroxil 882 mg	AL Placebo
Started	207	208	208
Completed	130	135	95
Not completed	77	73	113
Adverse event, serious fatal	-	-	1
Consent withdrawn by subject	35	29	22
Physician decision	3	-	-
Adverse event, non-fatal	14	6	36
Non-compliance with study drug	-	-	1
Incarceration	-	3	-
LTFU, then returned for follow-up	-	-	1
Lost to follow-up	10	15	10
Lack of efficacy	9	17	38
Protocol deviation	6	3	4

Baseline characteristics

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Reporting group title

aripiprazole lauroxil 441 mg

Reporting group description

-

Reporting group title

aripiprazole lauroxil 882 mg

Reporting group description

-

Reporting group title

AL Placebo

Reporting group description

aripiprazole lauroxil-matched placebo

Reporting group values	aripiprazole lauroxil 441 mg	aripiprazole lauroxil 882 mg	AL Placebo	Total
Number of subjects	207	208	208	623
Age Categorical
Units: participants
<=18 years	0	0	0	0
Between 18 and 65 years	207	207	207	621
>=65 years	0	1	1	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	39.9 ± 10.13	39.7 ± 11.06	39.5 ± 11.85	-
Gender, Male/Female
Units: participants
Female	66	65	69	200
Male	141	143	139	423
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	1	1	2
Asian	24	28	29	81
Native Hawaiian or Other Pacific Islander	1	0	0	1
Black or African American	83	81	84	248
White	99	98	94	291
More than one race	0	0	0	0
Unknown or Not Reported	0	0	0	0
Region of Enrollment
Units: Subjects
United States	103	102	102	307
Philippines	16	21	16	53
Malaysia	7	7	10	24
Ukraine	29	29	32	90
Romania	5	6	6	17
Bulgaria	23	19	17	59
Russian Federation	24	24	25	73

End points

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Reporting group title

aripiprazole lauroxil 441 mg

Reporting group description

-

Reporting group title

aripiprazole lauroxil 882 mg

Reporting group description

-

Reporting group title

AL Placebo

Reporting group description

aripiprazole lauroxil-matched placebo

Primary: The change from Baseline at Day 85 in Positive and Negative Syndrome Scale (PANSS) total score

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End point title

The change from Baseline at Day 85 in Positive and Negative Syndrome Scale (PANSS) total score

End point description

The PANSS scale contains 30 questions, each containing an answer range of 1-7. A total PANSS score can range from between 30 to 210; a higher score indicates a worse disease condition.

End point type

Primary

End point timeframe

Data collected from baseline to day 85

End point values	aripiprazole lauroxil 441 mg	aripiprazole lauroxil 882 mg	AL Placebo
Number of subjects analysed	196	204	196
Units: units on a scale
least squares mean (standard error)	-20.9 ± 1.39	-21.8 ± 1.35	-9.8 ± 1.39

p-value

Statistical analysis description

Significant p-value, active (441 mg) vs placebo

Comparison groups

aripiprazole lauroxil 441 mg v AL Placebo

Number of subjects included in analysis

392

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Confidence interval

sides

2-sided

lower limit

-

upper limit

-

p-value

Statistical analysis description

Significant p-value, active (882 mg) vs placebo

Comparison groups

aripiprazole lauroxil 882 mg v AL Placebo

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Confidence interval

sides

2-sided

lower limit

-

upper limit

-

Secondary: Clinical Global Impression - Improvement (CGI-I) Scores at Day 85

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End point title

Clinical Global Impression - Improvement (CGI-I) Scores at Day 85

End point description

The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the study. Participants were categorized as: "1: very much improved"; "2: much improved"; "3: minimally improved"; "4: no change"; "5: minimally worse"; "6: much worse"; or "7: very much worse".

End point type

Secondary

End point timeframe

85 Days

End point values	aripiprazole lauroxil 441 mg	aripiprazole lauroxil 882 mg	AL Placebo
Number of subjects analysed	196	204	196
Units: participants in category
number (not applicable)
CGI Score: Very much improved	27	25	15
CGI Score: Much improved	68	81	33
GCI Score: Minimally improved	45	52	43
CGI Score: No change	32	24	42
CGI Score: Minimally worse	11	16	37
CGI Score: Much worse	12	5	23
CGI Score: Very much worse	1	1	3

p-value active (441 mg) v placebo

Comparison groups

aripiprazole lauroxil 441 mg v AL Placebo

Number of subjects included in analysis

392

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Wilcoxon rank sum test based on LOCF

Confidence interval

sides

2-sided

lower limit

-

upper limit

-

Notes
[1] - significant p-value, active vs placebo

p-value active (881 mg) v placebo

Comparison groups

aripiprazole lauroxil 882 mg v AL Placebo

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[2]

Method

Wilcoxon rank sum test based on LOCF

Confidence interval

sides

2-sided

lower limit

-

upper limit

-

Notes
[2] - significant p-value, active vs placebo

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected during the 85-day treatment period.

Adverse event reporting additional description

One randomized subject was discontinued for a protocol violation prior to receiving IM study drug (placebo), and this subject was not included in the safety population. This changes the overall number of subjects in the placebo group to include 207.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

aripiprazole lauroxil 441 mg

Reporting group description

Intramuscular injection, given monthly

Reporting group title

placebo

Reporting group description

Intramuscular injection, given monthly

Reporting group title

aripiprazole lauroxil 882 mg

Reporting group description

Intramuscular injection, given monthly

Serious adverse events	aripiprazole lauroxil 441 mg	placebo	aripiprazole lauroxil 882 mg
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 207 (1.45%)	4 / 207 (1.93%)	4 / 208 (1.92%)
number of deaths (all causes)	0	1	0
number of deaths resulting from adverse events	0	0	0
Cardiac disorders
Angina unstable
subjects affected / exposed	1 / 207 (0.48%)	0 / 207 (0.00%)	0 / 208 (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
Nervous system disorders
Akathisia
subjects affected / exposed	0 / 207 (0.00%)	0 / 207 (0.00%)	1 / 208 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Social circumstances
Victim of homicide
subjects affected / exposed	0 / 207 (0.00%)	1 / 207 (0.48%)	0 / 208 (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
Gastrointestinal disorders
Peritoneal adhesions
subjects affected / exposed	1 / 207 (0.48%)	0 / 207 (0.00%)	0 / 208 (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
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	0 / 207 (0.00%)	0 / 207 (0.00%)	1 / 208 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Drug Abuse
subjects affected / exposed	0 / 207 (0.00%)	0 / 207 (0.00%)	1 / 208 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 207 (0.00%)	1 / 207 (0.48%)	0 / 208 (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
Suicide attempt
subjects affected / exposed	0 / 207 (0.00%)	1 / 207 (0.48%)	0 / 208 (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
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 207 (0.48%)	0 / 207 (0.00%)	0 / 208 (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
Pneumonia
subjects affected / exposed	0 / 207 (0.00%)	1 / 207 (0.48%)	0 / 208 (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
Hypoglycaemia
subjects affected / exposed	0 / 207 (0.00%)	0 / 207 (0.00%)	1 / 208 (0.48%)
occurrences causally related to treatment / all	0 / 0	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	aripiprazole lauroxil 441 mg	placebo	aripiprazole lauroxil 882 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	66 / 207 (31.88%)	76 / 207 (36.71%)	68 / 208 (32.69%)
Nervous system disorders
Akathisia
subjects affected / exposed	24 / 207 (11.59%)	9 / 207 (4.35%)	23 / 208 (11.06%)
occurrences all number	26	9	30
Headache
subjects affected / exposed	17 / 207 (8.21%)	17 / 207 (8.21%)	18 / 208 (8.65%)
occurrences all number	20	20	22
Psychiatric disorders
Agitation
subjects affected / exposed	3 / 207 (1.45%)	11 / 207 (5.31%)	3 / 208 (1.44%)
occurrences all number	4	11	3
Anxiety
subjects affected / exposed	6 / 207 (2.90%)	14 / 207 (6.76%)	11 / 208 (5.29%)
occurrences all number	11	16	14
Insomnia
subjects affected / exposed	20 / 207 (9.66%)	24 / 207 (11.59%)	25 / 208 (12.02%)
occurrences all number	26	29	27
Schizophrenia
subjects affected / exposed	12 / 207 (5.80%)	22 / 207 (10.63%)	5 / 208 (2.40%)
occurrences all number	13	22	5

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

01 Dec 2011

Reclassified previous secondary efficacy evaluations; clarified washout period for discontinuing current antipsychotics; changed the allowable time window for predose ECG measurement; adjusted order of clinical assessments during visits; changed exclusion criterion of baseline ECG; added a requirement that the site would develop a compliance plan to ensure that subjects adhered to oral dosing in the outpatient setting and returned to clinic for subsequent visits; allowed the injector to be unblinded, as long as the injector did not participate in the assessments, ratings, observations, or any other clinical assessments of the subject.

11 Oct 2012

Further clarify the purpose of the unblinded interim analysis; allow additional visits, hospitalization for psychosocial issues or respite care to improve subject retention; change allowable time windows for orthostatic vital sign measurements and postdose ECT measurements; adjust order of clinical assessments during visits; add exceptions to the definition of SAE, if the AE required inpatient hospitalization or prolongation of existing hospitalization.

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.

One randomized subject (placebo group) was discontinued for a protocol violation prior to receiving IM study drug.

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The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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