UMIN-CTR Clinical Trial

Public title

Investigation of biological and clinical predictor of antidepressant response for personalized medicine in depression ; a randomized controlled trial

Acronym

Genotype Utility Needed for Depression Antidepressant Medication (GUNDAM)

Scientific Title

Investigation of biological and clinical predictor of antidepressant response for personalized medicine in depression ; a randomized controlled trial

Scientific Title:Acronym

Genotype Utility Needed for Depression Antidepressant Medication (GUNDAM)

Region

Japan

Condition

Major depression

Classification by specialty

Psychiatry

Classification by malignancy

Others

Genomic information

YES

Narrative objectives1

Based on patient characteristics, subtype of depression and biological factor such as genetic factor and QEEG, we aimed to develop the personalized medicine and prescribed best therapeutic tool for each patient. That is, to establish algorithm for treatment of depression.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

Improvement of depressive symptom assessed by HAM-D

Key secondary outcomes

Adverse effect assessed by UKU
QIDS
NEO personality inventory
Social-cognitive function

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Active

Stratification

YES

Dynamic allocation

NO

Institution consideration

Blocking

Concealment

Numbered container method

No. of arms

3

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Depressive patients are randomly assigned to either mirtazapine or
SSRIs.

Interventions/Control_2

Non-responders after 4-week treatment are randomly assigned to either maintain the same treatment or augmentation.

Interventions/Control_3

Augmentation therapy are added to the subject who does not remit after 8-week treatment.

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

18

years-old

<=

Age-upper limit

75

years-old

>=

Gender

Male and Female

Key inclusion criteria

Drug naive patient (between 18 and 75 years old) with depression defined by DSN-IV whose HAM-D score are at least 14 .

Key exclusion criteria

Subjects with clinically significant unstable medical illness, pregnancy, a principal psychiatric diagnosis other than major depression, a history of substance abuse or dependence active within the previous 6 months, and electroconvulsive therapy within the previous 6 months were excluded.

Target sample size

300

Name of lead principal investigator

1st name	Masaki
Middle name
Last name	Kato

Organization

Kansai Medical University

Division name

Department of Neuropsychiatry

Zip code

570-8506

Address

10-15 Fumizonocho Moriguchi, Osaka

TEL

69921001

Email

pangaea1975@yahoo.co.jp

Name of contact person

1st name	Masaki
Middle name
Last name	Kato

Organization

Kansai Medical University

Division name

Department of Neuropsychiatry

Zip code

570-8506

Address

10-15, Fumizono-cho, Moriguchi City, Osaka

TEL

69921001

Homepage URL

Email

pangaea1975@yahoo.co.jp

Institute

Kansai Medical University Department of Neuropsychiatry

Institute

Department

Personal name

Organization

Self funding, Ministry for Scientific Research,SENSHIN Medical Research Foundation

Organization

Division

Category of Funding Organization

Other

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Medical Ethics Review Committee, Kansai Medical University

Address

10-15 Fumizonocho Moriguchi, Osaka

Tel

06-6992-1001

Email

katom@takii.kmu.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

関西医科大学付属滝井病院精神神経科（大阪府）

Date of disclosure of the study information

2011

Year

09

Month

27

Day

URL releasing protocol

http://www.journalofpsychiatricresearch.com/article/S0022-3956(16)30826-3/fulltext

Publication of results

Published

URL related to results and publications

http://www.journalofpsychiatricresearch.com/article/S0022-3956(16)30826-3/fulltext

Number of participants that the trial has enrolled

154

Results

Mirtazapine showed significantly faster improvement compared to SSRIs. Somnolence rate was higher in mirtazapine and nausea rate was higher in SSRIs. Combination therapy showed a more favorable time course than SSRIs monotherapy.

Results date posted

2023

Year

10

Month

07

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

From September 2011 through December 2014, a total of 207 patients were screened, 154 were enrolled and 141 took at least one post baseline HAM-D assessment during the step I study. Out of 126 patients who completed step I, 58 patient failed to reach response and were randomly assigned again and 45 patients (mirtazapine; n=13, SSRIs; n=12 and combination; n=20) had at least one post 4-week HAM-D assessment during the step IIa. On the other hand, 68 patients (mirtazapine; n=30 and SSRIs; n=38) reached response during the step I study and 66 patients continued the same SSRIs/mirtazapine monotherapy for another 4 weeks in step IIb. The baseline clinical and sociodemographic characteristics of subjects are presented in table 1. The mean age was 47.2 years, 48.9% were female and 22.7% were unemployed. Participants had moderate-to-severe depression, as indicated by a mean HAM-D17 score of 20.7 points. Over one-third had recurrent depression. Duration of current MDD episode was 8 months, total duration of MDD was 3.9 years and age at first episode was 43 years.

Participant flow

Participants
The subjects included to the study were 20-75 years old outpatients, met the diagnosis of major depressive disorder according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders (American Psychiatric Association, 1994), Japanese, scoring at least 14 in the 17-item Hamilton Rating Scale for Depression (HAM-D 17) (Hamilton, 1967) and had been free of psychotropic drugs for at least 14 days before entering into the study. Subjects with clinically significant unstable medical illness, pregnancy, a principal psychiatric diagnosis other than major depression, a history of substance abuse or dependence active within the previous 6 months, and electroconvulsive therapy within the previous 6 months were excluded. The diagnoses were assigned by 2 independent senior psychiatrists and confirmed by a third psychiatrist.
Protocol treatment
In step I study, participants were randomly assigned to treatment with one of two classes of antidepressant; mirtazapine or SSRIs (paroxetine or sertraline) in a 1:1 ratio (Figure 1). Mirtazapine was administered once daily at bedtime and paroxetine and sertraline was administered once daily after dinner. The initial dose was 15mg/day for mirtazapine, 10 mg/day for paroxetine and 25 mg/day for sertraline. The dose must be increased to 30 mg/day for mirtazapine, 20mg/day for paroxetine and 50mg/day for sertraline within 2weeks and could be increased up to 45mg/day for mirtazapine, 40mg/day for paroxetine and 100 mg/day for sertraline in 4 weeks (maximum dose approved in Japan).
In step II study, patients who reached response, defined as an at least 50% decrease or remission, defined as 7 or less in HAM-D 17 total score after 4 weeks medication, continued the same monotherapy (Step IIb) and patients who failed to reach response or remission after 4 weeks, were randomly assigned to continue mirtazapine/ SSRIs monotherapy or combine them (Step IIa). Additional antidepressant was increased to minimally-effective dose (mirtazapine 30mg/day, paroxetine 20mg/day and sertraline 50mg/day) and could be adjusted based on clinical symptoms.
Concomitant psychotropic drugs were not allowed, except a low dose of sleep aids at bedtime for both Steps I and II. The patients' adherence to the study medication was monitored by counting the returned tablets and the patients' reports of non-adherence.

Adverse events

Rate of sleepiness/sedation was significantly higher in mirtazapine prescribed subject (40.3%) compared to SSRIs (18.1%). Logistic regression analysis showed that mirtazapine (p=0.004, OR=3.3 95%CI=1.5-7.6) and male sex (p<0.001, OR=4.6 95%CI=1.9-10.7) contributed significantly to the higher rate of this adverse evet. But no difference was observed for more than 2 points worsening in rate of sleepiness/sedation between treatment groups (MIR=7.5%, SSRIs= 2.8%). Rate of nausea/vomiting was not observed for mirtazapine and this was significantly lower (p<0.0001) than for SSRIs (19.4%). For SSRIs, the rate of 2 point worsening was 6.9%. Both the rate of accommodation disturbances and erectile dysfunction/dry vagina for mirtazapine group was 0% and lower than SSRIs group (6.9% and 5.6%, respectively), but this differences were not statistically significant. Rate of drop out by any reason and by adverse event were 18.2% (mirtazapine=22.1%, SSRIs=14.3%) and 13.0% (mirtazapine=15.1%, SSRIs=10.1%), respectively without significant difference between treatment groups. No significant difference was observed for any other adverse event.

Outcome measures

Treatment outcome measure
All patients were evaluated at baseline and bi-weekly thereafter until the end of the study using the HAM-D 17. The primary efficacy outcome was change in HAM-D 17 total score from baseline to week 4 for step I and from week 4 to week 8 for step II study. Secondary efficacy outcomes were rate of remission, defined as HAMD17 score <7, at week 2, 4, 6 and 8 and also the rate of response defined as a 50% decrease in severity from baseline at week 2 and 4. The HAM-D assessment was performed by trained senior psychiatrists (M.K., S.S., H.B., K.N. and Y.T.).

Side effect and adverse event measure
All adverse events volunteered or observed during the study were recorded, together with their severity and duration. The use of the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale at baseline and bi-weekly ensured systematic collection of adverse events data. Other safety measures included 12-lead ECG and clinical laboratory assessments (hematology and serum chemistry) at baseline, week 4 and week8.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Main results already published

Date of protocol fixation

2011

Year

01

Month

01

Day

Date of IRB

2011

Year

02

Month

03

Day

Anticipated trial start date

2011

Year

09

Month

01

Day

Last follow-up date

2015

Year

04

Month

30

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2011

Year

09

Month

27

Day

Last modified on

2023

Year

10

Month

07

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007612