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Clinical Trial Results:
A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Rapastinel in the Prevention of Relapse in Patients with Major Depressive Disorder

Summary
EudraCT number	2018-000064-28
Trial protocol	HU SE SK PL BG
Global end of trial date	11 Jul 2019

Results information
Results version number	v1(current)
This version publication date	27 Jul 2020
First version publication date	27 Jul 2020
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

RAP-MD-33

ISRCTN number

-

US NCT number

NCT03614156

WHO universal trial number (UTN)

-

Sponsor organisation name

Allergan

Sponsor organisation address

1st Floor, Marlow International, The Parkway, Marlow, Marlow Buckinghamshire SL7 1YL, United Kingdom, SL7 1YL

Public contact

Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@Allergan.com

Scientific contact

Therapeutic Area, Head, Allergan, 001 862-261-7000, IR-CTRegistration@allergan.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

11 Jul 2019

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

11 Jul 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of this trial is to evaluate the efficacy, safety, and tolerability of 450 milligrams (mg) or 225 mg of Rapastinel compared to placebo in the prevention of relapse in participants with major depressive disorder (MDD).

Protection of trial subjects

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

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

02 Aug 2018

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Hungary: 11

Country: Number of subjects enrolled

Japan: 11

Country: Number of subjects enrolled

United States: 335

Country: Number of subjects enrolled

Poland: 1

Country: Number of subjects enrolled

Slovakia: 5

Worldwide total number of subjects

363

EEA total number of subjects

17

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)

330

From 65 to 84 years

33

85 years and over

0

Subject disposition

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Recruitment details

Patients from RAP-MD-33 completed one of the rapastinel lead-in studies - RAP-MD-30, RAP-MD-31, or RAP-MD-32.

Screening details

A total of 363 patients enrolled in the Open Label Treatment Period (OLTP). Of these, 209 completed the OLTP and 137 entered the Double Blind Treatment Period (DBTP) and were randomized.

Number of subjects started

363

Intermediate milestone: Number of subjects

Completed Open Label Treatment Period: 209

Number of subjects completed

137

Reason: Number of subjects

Adverse event, non-fatal: 7

Reason: Number of subjects

Lack of efficacy: 18

Reason: Number of subjects

Consent withdrawn by subject: 36

Reason: Number of subjects

Lost to follow-up: 10

Reason: Number of subjects

Protocol deviation: 2

Reason: Number of subjects

Protocol-specified withdrawal met: 6

Reason: Number of subjects

Non-compliance with study drug: 1

Reason: Number of subjects

Study terminated by sponsor: 74

Reason: Number of subjects

Did not meet stability criteria: 72

Period 1 title

Double-Blind Treatment Period (DBTP) (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

Placebo weekly

Arm description

Placebo (prefilled syringe, weekly IV administration)

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Intravenous use

Dosage and administration details

Intravenous IV administration once per week.

Rapastinel clinically driven schedule

Arm description

Rapastinel 450 mg or 225 mg (prefilled syringe, clinically driven schedule IV administration, variable interval, placebo on intervening weeks)

Arm type

Experimental

Investigational medicinal product name

Rapastinel

Investigational medicinal product code

AGN-241659 (previously GLYX-13)

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Intravenous use

Dosage and administration details

Rapastinel intravenous IV administration

Rapastinel weekly

Arm description

Rapastinel 450 mg or 225 mg (prefilled syringe, weekly intravenous IV administration)

Arm type

Experimental

Investigational medicinal product name

Rapastinel

Investigational medicinal product code

AGN-241659 (previously GLYX-13)

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Intravenous use

Dosage and administration details

Rapastinel intravenous IV administration

Number of subjects in period 1 ^[1]	Placebo weekly	Rapastinel clinically driven schedule	Rapastinel weekly
Started	40	42	55
Entered Safety Follow Up Period	26	30	35
Completed	10	11	10
Not completed	30	31	45
Consent withdrawn by subject	4	1	1
Adverse event, non-fatal	2	-	1
Miscellaneous Reasons	1	-	-
Study terminated by sponsor	22	26	38
Lost to follow-up	-	3	4
Protocol deviation	1	1	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The baseline period consists only of those 137 participants who were randomized out of the overall 363 enrolled participants.

Baseline characteristics

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Reporting group title

Placebo weekly

Reporting group description

Placebo (prefilled syringe, weekly IV administration)

Reporting group title

Rapastinel clinically driven schedule

Reporting group description

Rapastinel 450 mg or 225 mg (prefilled syringe, clinically driven schedule IV administration, variable interval, placebo on intervening weeks)

Reporting group title

Rapastinel weekly

Reporting group description

Rapastinel 450 mg or 225 mg (prefilled syringe, weekly intravenous IV administration)

Reporting group values	Placebo weekly	Rapastinel clinically driven schedule	Rapastinel weekly	Total
Number of subjects	40	42	55	137
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	33	40	53	126
From 65-84 years	7	2	2	11
85 years and over	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	47.0 ± 13.95	43.6 ± 12.57	43.9 ± 11.66	-
Sex: Female, Male
Units: Participants
Female	30	29	44	103
Male	10	13	11	34
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	1	0	0	1
Asian	3	2	2	7
Native Hawaiian or Other Pacific Islander	1	2	0	3
Black or African American	8	5	11	24
White	27	33	42	102
More than one race	0	0	0	0
Unknown or Not Reported	0	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	3	8	9	20
Not Hispanic or Latino	37	34	46	117
Unknown or Not Reported	0	0	0	0
Weight
Units: kg
arithmetic mean (standard deviation)	84.84 ± 17.856	85.88 ± 19.207	88.53 ± 19.240	-
Height
Units: cm
arithmetic mean (standard deviation)	168.31 ± 8.996	166.92 ± 9.858	168.47 ± 9.196	-
BMI
Units: kg/m^2
arithmetic mean (standard deviation)	29.89 ± 5.686	30.95 ± 7.289	31.15 ± 6.279	-

End points

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Reporting group title

Placebo weekly

Reporting group description

Placebo (prefilled syringe, weekly IV administration)

Reporting group title

Rapastinel clinically driven schedule

Reporting group description

Rapastinel 450 mg or 225 mg (prefilled syringe, clinically driven schedule IV administration, variable interval, placebo on intervening weeks)

Reporting group title

Rapastinel weekly

Reporting group description

Rapastinel 450 mg or 225 mg (prefilled syringe, weekly intravenous IV administration)

Primary: Time to First Relapse During the 52 Weeks of the Double-Blind Treatment Period (DBTP)

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End point title

Time to First Relapse During the 52 Weeks of the Double-Blind Treatment Period (DBTP) ^[1]

End point description

Time in days from randomization to relapse. The primary efficacy analysis will compare the time to relapse between placebo and rapastinel treatment groups using the log-rank test. Due to study termination, there are not enough events to allow for any statistically meaningful estimation of the Time to First Relapse. As a result, only the time to relapse at the 25th percentile is presented for each study arm, without confidence intervals.

End point type

Primary

End point timeframe

52 Weeks

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: Due to study termination, there are not enough events to allow for any meaningful statistical analysis.

End point values	Placebo weekly	Rapastinel clinically driven schedule	Rapastinel weekly
Number of subjects analysed	40	42	55
Units: Days(Time of Relapse at 25th percentile)
number (not applicable)	94	177	157

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The study consisted of an 8 to 16 week OLTP; followed by a randomized DBTP of up to 52 weeks; followed by a 2 week safety period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.2

Reporting group title

Open-Label Treatment Period

Reporting group description

Rapastinel 225 milligrams (mg) or 450 mg intravenous (IV) once a week during OLTP.

Reporting group title

Placebo weekly

Reporting group description

Placebo (prefilled syringe, weekly IV administration)

Reporting group title

Rapastinel clinically driven schedule

Reporting group description

Rapastinel 450 mg or 225 mg (prefilled syringe, clinically driven schedule IV administration, variable interval, placebo on intervening weeks)

Reporting group title

Rapastinel weekly

Reporting group description

Rapastinel 450 mg or 225 mg (prefilled syringe, weekly intravenous IV administration)

Serious adverse events	Open-Label Treatment Period	Placebo weekly	Rapastinel clinically driven schedule	Rapastinel weekly
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 363 (1.10%)	1 / 40 (2.50%)	1 / 42 (2.38%)	0 / 55 (0.00%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Nervous system disorders
Partial seizures
subjects affected / exposed	1 / 363 (0.28%)	0 / 40 (0.00%)	0 / 42 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 363 (0.00%)	1 / 40 (2.50%)	0 / 42 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 363 (0.28%)	0 / 40 (0.00%)	0 / 42 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	1 / 363 (0.28%)	0 / 40 (0.00%)	0 / 42 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 363 (0.28%)	0 / 40 (0.00%)	0 / 42 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Alcoholism
subjects affected / exposed	0 / 363 (0.00%)	0 / 40 (0.00%)	1 / 42 (2.38%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Open-Label Treatment Period	Placebo weekly	Rapastinel clinically driven schedule	Rapastinel weekly
Total subjects affected by non serious adverse events
subjects affected / exposed	44 / 363 (12.12%)	17 / 40 (42.50%)	9 / 42 (21.43%)	13 / 55 (23.64%)
Nervous system disorders
Headache
subjects affected / exposed	20 / 363 (5.51%)	3 / 40 (7.50%)	1 / 42 (2.38%)	3 / 55 (5.45%)
occurrences all number	23	5	1	4
Dizziness
subjects affected / exposed	1 / 363 (0.28%)	2 / 40 (5.00%)	0 / 42 (0.00%)	0 / 55 (0.00%)
occurrences all number	2	2	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 363 (0.55%)	2 / 40 (5.00%)	0 / 42 (0.00%)	0 / 55 (0.00%)
occurrences all number	2	2	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	1 / 363 (0.28%)	4 / 40 (10.00%)	0 / 42 (0.00%)	1 / 55 (1.82%)
occurrences all number	1	4	0	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	4 / 363 (1.10%)	2 / 40 (5.00%)	1 / 42 (2.38%)	2 / 55 (3.64%)
occurrences all number	4	2	1	2
Vomiting
subjects affected / exposed	2 / 363 (0.55%)	3 / 40 (7.50%)	0 / 42 (0.00%)	1 / 55 (1.82%)
occurrences all number	2	3	0	1
Abdominal pain upper
subjects affected / exposed	2 / 363 (0.55%)	2 / 40 (5.00%)	1 / 42 (2.38%)	0 / 55 (0.00%)
occurrences all number	3	2	1	0
Gastritis
subjects affected / exposed	0 / 363 (0.00%)	2 / 40 (5.00%)	0 / 42 (0.00%)	0 / 55 (0.00%)
occurrences all number	0	2	0	0
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection
subjects affected / exposed	18 / 363 (4.96%)	1 / 40 (2.50%)	4 / 42 (9.52%)	3 / 55 (5.45%)
occurrences all number	19	1	4	3
Psychiatric disorders
Insomnia
subjects affected / exposed	15 / 363 (4.13%)	3 / 40 (7.50%)	1 / 42 (2.38%)	0 / 55 (0.00%)
occurrences all number	16	3	1	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	26 / 363 (7.16%)	0 / 40 (0.00%)	4 / 42 (9.52%)	5 / 55 (9.09%)
occurrences all number	31	0	4	5
Bronchitis
subjects affected / exposed	2 / 363 (0.55%)	2 / 40 (5.00%)	0 / 42 (0.00%)	1 / 55 (1.82%)
occurrences all number	2	2	0	1

More information

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Were there any global substantial amendments to the protocol? No

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.

Due to study termination, the target number of participants needed to achieve target power and statistically reliable results was not met.

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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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