Clinical Trial Results:
Interventional, randomised, double-blind, parallel-group, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of brexpiprazole (1 and 3 mg/day) as adjunctive treatment in elderly patients with major depressive disorder with an inadequate response to antidepressant treatment THE STUDY WAS PREMATURELY TERMINATED AND NO FIRM CONCLUSIONS CAN BE DRAWN REGARDING SAFETY AND EFFICACY

Trial information Top of page
Trial identification
Sponsor protocol code	14571A
Additional study identifiers
ISRCTN number	-
US NCT number	NCT01837797
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	H. Lundbeck A/S
Sponsor organisation address	Ottiliavej 9,, Valby, Denmark,
Public contact	LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, 45 36301 311, LundbeckClinicalTrials@lundbeck.com
Scientific contact	LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, 45 36301 311, LundbeckClinicalTrials@lundbeck.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	22 May 2014
Is this the analysis of the primary completion data?	Yes
Primary completion date	22 May 2014
Global end of trial reached?	Yes
Global end of trial date	22 May 2014
Was the trial ended prematurely?	Yes
General information about the trial
Main objective of the trial	Efficacy on depressive symptoms of brexpiprazole versus placebo as adjunctive treatment to antidepressants in elderly patients with an inadequate response to antidepressant treatment
Protection of trial subjects	The trial was conducted in accordance with the Declaration of Helsinki (2008) and ICH Good Clinical Practice (1996)
Background therapy	standard antidepressant treatment, specifically; escitalopram, fluoxetine, sertraline, paroxetine IR, venlafaxine XR, duloxetine
Evidence for comparator	-
Actual start date of recruitment	15 Apr 2013
Long term follow-up planned	Yes
Long term follow-up rationale	Safety
Long term follow-up duration	1 Years
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Poland: 10
Country: Number of subjects enrolled	Romania: 2
Country: Number of subjects enrolled	Slovakia: 4
Country: Number of subjects enrolled	Sweden: 10
Country: Number of subjects enrolled	United Kingdom: 3
Country: Number of subjects enrolled	Bulgaria: 1
Country: Number of subjects enrolled	Estonia: 3
Country: Number of subjects enrolled	Finland: 3
Country: Number of subjects enrolled	Germany: 9
Country: Number of subjects enrolled	Lithuania: 3
Country: Number of subjects enrolled	United States: 67
Country: Number of subjects enrolled	Ukraine: 4
Country: Number of subjects enrolled	Russian Federation: 10
Worldwide total number of subjects	129
EEA total number of subjects	48
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)	0
From 65 to 84 years	129
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Patients were recruited from the investigator's own patient population, via advertisement (if allowed in the country), via general pratitioners or or referrals
Pre-assignment
Screening details	The study consisted of a screening period (could last from 3 to 28 days)
Period 1
Period 1 title	Periode 1
Is this the baseline period?	Yes
Allocation method	Non-randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator
Arms
Arm title	antidepressants treatment with double-blind study treatment
Arm description	The patients received open-label treatment with one of six commercially available antidepressant antidepressant treatments (ADT) together with double-blind study treatment
Arm type	Non-investigational Medicinal Products
Investigational medicinal product name	Duloxetine (Cymbalta)
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	60 mg/day, capsules, orally
Investigational medicinal product name	Escitalopram (Cipralex or Lexapro)
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	5 or 10 mg/day, tablets, orally
Investigational medicinal product name	Fluoxetine (Prozac)
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	20 or 40 mg/day, capsules, orally
Investigational medicinal product name	Paroxetine (Paxil or Seroxat)
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	20, 30 or 40mg/day, orally, tablets
Investigational medicinal product name	Sertraline (Lustral or Zoloft)
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	50, 100 or 150 mg/day
Investigational medicinal product name	Venlafaxine (Effexor XL or Effexor XR)
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	75, 150 or 225 mg/day, capsules, orally
Investigational medicinal product name	Placebo
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	once daily, tablets, orally for 8 or 10 weeks
Number of subjects in period 1 antidepressants treatment with double-blind study treatment Started 129 Completed 27 Not completed 102      Consent withdrawn by subject 6      Withdrew consent before ADT 1      Adverse event, non-fatal 9      Administrative or other 76      Other 10
Period 2
Period 2 title	Period 2
Is this the baseline period?	No
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator
Arms
Are arms mutually exclusive	Yes
Arm title	Brexpiprazole 1 mg and ADT
Arm description	Brexpiprazole adjunct to continued open-label treatment with a commercially available ADT received in Period 1
Arm type	Experimental
Investigational medicinal product name	Brexpiprazole
Investigational medicinal product code	Lu AF41156
Other name	OPC-34712
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	1 mg once daily, tablets, orally
Arm title	Brexpiprazole 3 mg and ADT
Arm description	Brexpiprazole adjunct to continued open-label treatment with a commercially available ADT received in Period 1
Arm type	Experimental
Investigational medicinal product name	Brexpiprazole
Investigational medicinal product code	Lu AF41156
Other name	OPC-34712
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	3 mg once daily, tablets, orally
Arm title	Placebo and ADT
Arm description	Placebo adjunct to continued open-label treatment with a commercially available ADT
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	once daily, tablets, orally
Number of subjects in period 2 [1] Brexpiprazole 1 mg and ADT Brexpiprazole 3 mg and ADT Placebo and ADT Started 3 6 6 Completed 1 1 1 Not completed 2 5 5      Adverse event, non-fatal - 1 -      The study was prematurely terminated 2 4 5
Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Only patients with prospectively assessed inadequate response were randomised to Period 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Periode 1
Reporting group description	-
Reporting group values Periode 1 Total Number of subjects 129 129 Age categorical Units: Subjects     In utero 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0     Newborns (0-27 days) 0 0     Infants and toddlers (28 days-23 months) 0 0     Children (2-11 years) 0 0     Adolescents (12-17 years) 0 0     Adults (18-64 years) 0 0     From 65-84 years 129 129     85 years and over 0 0 Age continuous Units: years     arithmetic mean (standard deviation) 70 ( 4.75 ) - Gender categorical Units: Subjects     Female 99 99     Male 30 30

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	antidepressants treatment with double-blind study treatment
Reporting group description	The patients received open-label treatment with one of six commercially available antidepressant antidepressant treatments (ADT) together with double-blind study treatment
Reporting group title	Brexpiprazole 1 mg and ADT
Reporting group description	Brexpiprazole adjunct to continued open-label treatment with a commercially available ADT received in Period 1
Reporting group title	Brexpiprazole 3 mg and ADT
Reporting group description	Brexpiprazole adjunct to continued open-label treatment with a commercially available ADT received in Period 1
Reporting group title	Placebo and ADT
Reporting group description	Placebo adjunct to continued open-label treatment with a commercially available ADT

End points Top of page

Primary: Number of treatment-emergent adverse events Top of page
End point title	Number of treatment-emergent adverse events [1]
End point description	The primary endpoint was efficacy, however the study was prematurely terminated and the limited number of enrolled patients resulted in insufficient data for meaningful analyses. Therefore treatment-emergent adverse events are disclosed
End point type	Primary
End point timeframe	First dose to follow-up (prematurely terminated)
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 comparison between parameters were performed
End point values Brexpiprazole 1 mg and ADT Brexpiprazole 3 mg and ADT Placebo and ADT Number of subjects analysed 3 6 6 Units: Number 5 2 3
No statistical analyses for this end point

Primary: Number of treatment-emergent adverse events Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	First dose to follow-up
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	16.1
Reporting groups
Reporting group title	Placebo + ADT
Reporting group description	Placebo + ADT
Reporting group title	Brex 3 mg + ADT
Reporting group description	Brex 3 mg + ADT
Reporting group title	Brex 1 mg + ADT
Reporting group description	Brex 1 mg + ADT
Serious adverse events Placebo + ADT Brex 3 mg + ADT Brex 1 mg + ADT Total subjects affected by serious adverse events      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 3 (0.00%)      number of deaths (all causes) 0 0 0      number of deaths resulting from adverse events 0 0 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Placebo + ADT Brex 3 mg + ADT Brex 1 mg + ADT Total subjects affected by non serious adverse events      subjects affected / exposed 2 / 6 (33.33%) 2 / 6 (33.33%) 2 / 3 (66.67%) Investigations Weight increased alternative assessment type: Non-systematic      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1 Injury, poisoning and procedural complications Accidental overdose alternative assessment type: Non-systematic      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Nervous system disorders Dizziness alternative assessment type: Non-systematic      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1 Parkinson's disease alternative assessment type: Non-systematic      subjects affected / exposed 0 / 6 (0.00%) 1 / 6 (16.67%) 0 / 3 (0.00%)      occurrences all number 0 1 0 Tremor alternative assessment type: Non-systematic      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1 General disorders and administration site conditions Gait disturbance alternative assessment type: Non-systematic      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1 Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease alternative assessment type: Non-systematic      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Dyspnoea alternative assessment type: Non-systematic      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1 Psychiatric disorders Bruxism alternative assessment type: Non-systematic      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Insomnia alternative assessment type: Non-systematic      subjects affected / exposed 0 / 6 (0.00%) 1 / 6 (16.67%) 0 / 3 (0.00%)      occurrences all number 0 1 0

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
22 May 2013	The main reason for the amendment was to correct errors and clarify the current protocol text in various sections of the protocol
Interruptions (globally)
Were there any global interruptions to the trial? Yes
Date Interruption Restart date 01 Apr 2014 The study was prematurely terminated because of recruitment challenges -
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
Early termination leading to a small number analysed; only AEs reported

More information Top of page