Yonemoto et al. Trials (2015) 16:459
DOI 10.1186/s13063-015-0985-6

TRIALSUPDATE

Open Access

Strategic use of new generation
antidepressants for depression: SUN(^_^) D
protocol update and statistical analysis plan
Naohiro Yonemoto1,2, Shiro Tanaka3, Toshi A. Furukawa4,5*, Tadashi Kato6, Akio Mantani7, Yusuke Ogawa4,
Aran Tajika4, Nozomi Takeshima4, Yu Hayasaka4, Kiyomi Shinohara4, Kazuhira Miki8, Masatoshi Inagaki9,
Shinji Shimodera10, Tatsuo Akechi11, Mitsuhiko Yamada1, Norio Watanabe12, Gordon H. Guyatt13
and for the SUN(^_^)D Investigators

Abstract
Background: SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessorblinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the
first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two
randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line
antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for thesecond-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was
published in 2011, and we hereby report its updated protocol including the statistical analysis plan.
Results: We implemented two important changes to the original protocol. One is about the required sample size,reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primaryand secondary outcomes in order to make the report of the main trial results as pertinent and interpretable aspossible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate
reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary
outcomes and their analyses. We will convene the blind interpretation committee before the randomization code isbroken.
Conclusion: This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D
trial in order to avoid reporting bias and data-driven results.
Trial registration: ClinicalTrials.gov: NCT01109693 (registered on 21 April 2010).

UpdateThis paper provides the updated protocol and the detailed statistical analysis plan for the Strategic Use of
New generation antidepressants for Depression, SUN(^_^)D, randomized controlled trial, a pragmatic megatrial examining the optimum treatment strategy for the* Correspondence: furukawa@kuhp.kyoto-u.ac.jp
4
Department of Health Promotion and Human Behavior, Kyoto University
Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho,
Sakyo-ku, Kyoto 606-8501, Japan
5
Department of Clinical Epidemiology, Kyoto University Graduate School of
Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto
606-8501, Japan
Full list of author information is available at the end of the article

first- and second-line treatments for unipolar major
depressive episodes. The original protocol was publishedin Trials in 2011 [1], and we hereby report its updated
protocol including the statistical analysis plan, as wewould like to implement two important changes to theoriginal protocol. One change is about the required sample size, reflecting the smaller number of dropouts than
had been expected. Another change is in the organizationof the primary and secondary outcomes in order to makethe report of the main trial results as pertinent and interpretable as possible for clinical practices.
The trial completed recruitment of all participants on
13 March 2015, and completion of the last follow-up is© 2015 Yonemoto et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Yonemoto et al. Trials (2015) 16:459

expected in September 2015. This updated protocol andstatistical analysis plan were drafted without knowledgeof the randomization code, which will not be broken before acceptance of the current paper for publication.

Trial overview
Trial design

SUN(^_^)D is an assessor-blinded, parallel-group, multicenter randomized controlled trial [1]. The trial has
three steps with two randomizations (Fig. 1). Randomizations were performed at first recruitment for Step I(cluster randomization by site) and at start of Step II(individual randomization). Step I has two arms, inwhich sertraline will be started from 25 mg/d and titrated up to 50 mg/d or up to 100 mg/d, the minimum
and the maximum of the standard prescription range inJapan, respectively. Step II has three arms, in which
sertraline will be continued as in Step I, mirtazapine will
be added to sertraline, or sertraline will be switched tomirtazapine. In Step III, all the treatments will be at thediscretion of the treating physician.
Treatment of a major depressive episode is commonly
divided into the acute phase treatment, which aims at
the prompt reduction of acute symptoms, and the continuation treatment, which not only seeks to reduce further the symptoms but also to prevent symptom relapses[2, 3]. The acute phase treatment usually lasts 6 to 12
weeks, and it is recommended that the continuation treatment be continued 4 to 9 months after the acute phasetreatment [2, 3]. In our study, therefore, Steps I and II

Fig. 1 Flow diagram of the trial

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represent the acute phase treatment, whereas Step III corresponds with the continuation treatment.
EthicsThis study is being conducted in accordance with the
Declaration of Helsinki and its amendments as well as
the Ethics Guideline for Clinical Research (2008 revision,
Ministry of Health, Labor and Welfare, Japan). Written
informed consent has been obtained from each participant after full explanation of the purpose and the procedures of the study.
This study has been approved by the Ethics Committeeof Kyoto University Graduate School of Medicine (C446),
Institutional Review Board of Nagoya City University
Hospital (45-10-0004), Ethics Committee of Kochi Medical
School (22-96), Ethics Committee of Kumamoto University
Graduate School of Life Sciences (Senshin 1341), Institutional Review Board of Yatsushiro Kosei Hospital, Ethics
Committee of Yuge Hospital (86), Ethics Committee of
Kurume University (11151), Ethics Committee of Saint
Lucia Hospital, Ethics Committee of Hiroshima University
Hospital (Rin 297), Institutional Review Board of The
University of Tokyo Hospital (P2011062-11X), Ethics
Committee of Toho University School of Medicine (23053),
and Institutional Review Board of Hokkaido University
Hospital (Ji 011-0292).
Funding

This trial was funded by a Grant-in-Aid from the Ministry of Health, Labor and Welfare, Japan (H22-Seishin-

Yonemoto et al. Trials (2015) 16:459

Ippan-008) (from April 2010 to March 2012) and by aresearch project “Pragmatic Psychopharmacotherapy
Research” of the Japan Foundation for Neuroscienceand Mental Health (from April 2012 to present). The“Pragmatic Psychopharmacotherapy Research” project
has received donations from Asahi Kasei Pharma, MSD,
Otsuka Pharmaceutical, GlaxoSmithKline, Shionogi, Taisho
Pharmaceutical, Mitsubishi Tanabe Pharma, Pfizer, Eli-Lilly,
Meiji Seika Pharma, Mochida Pharmaceutical, and Janssen
Pharmaceutical as of May 2015.

Study objectives

As presented in the published protocol [1], the objectiveof this trial is to establish the optimum first-line andsecond-line antidepressant treatment strategy among patients with a nonpsychotic unipolar major depressive
episode. As the SUN(^_^)D trial involved two randomizations, we will report the main results of the trial as
two separate reports.
REPORT #1 will be entitled “Optimum Target Dosefor Initial Sertraline Treatment for Depression: The
SUN(^_^)D Trial.”
This report will answer the following clinical question:
Which is a superior dosing strategy for the first-line treatment with sertraline, aiming at the lowest or the highestof the standard prescription range, through the acutephase treatment as well as the continuation treatment?
We will compare the following two interventions:
1. Intervention 1: The strategy is to start sertraline at
25 mg/d, with the intention of titrating it up to 50
mg/d where possible by week 3, continuing it up to
week 9, and then prescribing at the treating
physician’s discretion up to week 25.
2. Intervention 2: The strategy is to start sertraline at
25 mg/d, with the intention of titrating it up to 100
mg/d where possible by week 3, continuing it up to
week 9, and then prescribing at treating physician’s
discretion up to week 25.
In order to examine the effect of the choice of the initial dosing strategy of the first-line treatment with sertraline through the acute and continuation treatment
phases, REPORT #1 will focus on the participants in theblue-shaded cells in Fig. 1.
REPORT #2 will be entitled “Continue, Switch orAugment after Initial Failure to Remit on First-line
Treatment in Depression: The SUN(^_^)D Trial.”
This report will answer the following clinical question: What is the best second-line treatment forpatients with no or partial initial response to the firstline treatment with sertraline through the acute phasetreatment as well as the continuation treatment?

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We will compare intervention 1 with intervention 2,
intervention 2 with intervention 3, and intervention 3
with intervention 1 (that is, all combinations without
any preferential ordering in importance):
1. Intervention 1: The strategy is to continue sertraline
at week 3 and up to week 9, and then prescribing at
the treating physician’s discretion up to week 25.
2. Intervention 2: The strategy is to switch sertraline tomirtazapine at week 3 and up to week 9, and thenprescribing at the treating physician’s discretion up
to week 25.
3. Intervention 3: The strategy is to add mirtazapine tosertraline at week 3 and up to week 9, and thenprescribing at the treating physician’s discretion up
to week 25.
REPORT #2 will therefore compare the three intervention arms at double borders in Fig. 1 through the acuteand continuation treatment phases.

Outcomes
Outcome measures
Patient health questionnaire-9

The Patient Health Questionnaire-9 (PHQ9) was developed
as a self-report version of the Primary Care Evaluation of
Mental Disorders (PRIME-MD) [4, 5]. The depression
module of the PHQ is called PHQ9 and consists of the nine
diagnostic criteria items of the DSM-IV. Each item is rated
between 0 = “not at all” through 3 = “nearly every day,”making the total score range from 0 to 27.
Kroenke and his colleagues [6] have provided the following rules of thumb for interpreting the continuous
PHQ9 scores:
0 to 4 no depression
5 to 9 mild depression
10 to 14 moderate depression
15 to 19 moderately severe depression
20 to 27 severe depression
In this trial, PHQ9 and FIBSER will be administered
four times (at week 1, week 3, week 9 and week 25) by
the blinded central rater via telephone [7].

Frequency, intensity, and burden of side effects rating

The Frequency, Intensity, and Burden of Side Effects
Rating (FIBSER) was originally used in STAR*D [8, 9] asa global rating scale for side effects. This is an assessorrated scale, and the Japanese translation has not undergone back translation. Each item is rated in seven gradesof severity.

Yonemoto et al. Trials (2015) 16:459

Beck depression inventory-II

The Beck Depression Inventory-II (BDI-II) is a 21-item
self-report instrument to measure the severity of depression [10, 11]. The time frame for evaluation is set to thepast 2 weeks, including the day of assessment. Each itemin the BDI-II has a series of four statements, which describe symptom severity along an ordinal continuum
from absent or mild (a score of 0) to severe (a score of3). The total score therefore ranges from 0 through 63.
In this trial, BDI-II will be filled in by the patient at
each visit (unblinded).
Columbia classification algorithm for suicide assessment

The Columbia Classification Algorithm for Suicide Assessment (C-CASA) is a classification system that utilizes definitions of suicidality [12]. The C-CASA has
eight categories that distinguish suicidal events from
nonsuicidal events and indeterminate or potentially suicidal events. The scoring is a binary (yes or no) for each
item.
Serious adverse events

A serious adverse event is defined here as “an adverse
event that may lead to death or to enduring severe impairment depending on the patient’s conditions and circumstances” and will include the following:
1. Death
2. Life-threatening event
3. Hospitalization or the prolongation of
hospitalization
4. Event leading to enduring and severe impairment
and dysfunction
5. Congenital malformation
The scoring is a binary yes or no for each item.
Allowance of timing of outcome assessments

Assessments at week 3, 9 and 25 may be made within
the following time frames after week 1:
1. ± 4 days for assessments at weeks 3 through 9
2. ± 14 days for assessments after week 9
If the allowance is violated, we will report it as a deviation from protocol.

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REPORT #2: Change in PHQ9 from 3 through 9 weeks
Secondary outcomes

Secondary outcomes for REPORTS #1 and #2 are summarized below from the viewpoint of the acute phasetreatment (up to 9 weeks) and that of the acute throughcontinuation treatments (up to 25 weeks).
REPORT #1
Report #1 will include the following:
1. For the acute phase treatment(as an index of effectiveness)
1-1. Change in BDI-II from 1 through 9 weeks
1-2. Proportion of response (50 % or greater
reduction from week 1 in PHQ9) at week 3
and week 91-3. Proportion of remission (4 or less on PHQ9)
at week 3 and week 9(as an index of acceptability and safety)
1-4. Proportion of successful continuation of theallocated treatment up to week 3 and toweek 9
1-5. Change in FIBSER from 1 through 9 weeks
1-6. Incidence of suicidality as measured with CCASA between 1 and 9 weeks
1-7. Incidence of mania, hypomania and mixed
episodes between 1 and 9 weeks
1-8. Incidence of serious adverse events between 1
and 9 weeks.
2. For the acute-phase to continuation treatments,(as an index of effectiveness)
2-1. Proportion of remission (4 or less on PHQ9)
at week 25
2-2.Change in PHQ9 from 1 through 25 weeks
2-3. Change in BDI-II from 1 through 25 weeks(as an index of acceptability and safety)
2-4. Time to discontinuation of the allocatedtreatment by week 25
2-5. Time to discontinuation of any treatment by
week 25
2-6. Change in FIBSER from 1 through 25 weeks
2-7. Incidence of suicidality as measured with CCASA between 1 and 25 weeks
2-8. Incidence of mania, hypomania and mixed
episodes between 1 and 25 weeks
2-9. Incidence of serious adverse events between 1
and 25 weeks

Primary outcome

We conducted two randomizations in this trial, and will
therefore make two corresponding reports, each ofwhich will have its own primary outcome for the acutephase treatment as follows:
REPORT #1: Change in PHQ9 from 1 through 9 weeks

REPORT #2
Report #2 will include the following:
1. For the acute phase treatment,(as an index of effectiveness)
1-1.Change in BDI-II from 3 through 9 weeks

Yonemoto et al. Trials (2015) 16:459

1-2. Proportion of response (50 % or greater
reduction from week 1 in PHQ9) at week 91-3. Proportion of remission (four or fewer onPHQ9) at week 9(as an index of acceptability and safety)
1-4. Proportion of successful continuation of theallocated treatment up to week 91-5. Change in FIBSER from 3 through 9 weeks
1-6. Incidence of suicidality as measured with CCASA between 3 and 9 weeks
1-7. Incidence of mania, hypomania and mixed
episodes between 3 and 9 weeks
1-8. Incidence of serious adverse events between 3
and 9 weeks.
2. For the acute-phase to continuation treatments,(as an index of effectiveness)
2-1. Proportion of remission (4 or less on PHQ9)
at week 25
2-2.Change in PHQ9 from 3 through 25 weeks
2-3. Change in BDI-II from 3 through 25 weeks(as an index of acceptability and safety)
2-4. Time to discontinuation of the allocatedtreatment by week 25
2-5. Time to discontinuation of any treatment by
week 25
2-6. Change in FIBSER from 3 through 25 weeks
2-7. Incidence of suicidality as measured with CCASA between 3 and 25 weeks
2-8. Incidence of mania, hypomania and mixed
episodes between 3 and 25 weeks
2-9. Incidence of serious adverse events between 3
and 25 weeks
Sample size and power

The clinical question for REPORT #2 is the main hypothesis of this trial. Previous studies using PHQ9 in theacute phase treatment of major depression have shown
that, on average, the PHQ9 scores will drop from 15(SD = 5) at baseline to 10 (SD = 6) at the end of treatment, with a mean change of 5 (SD = 5). We expect a
difference of 20 % (1 point) in the PHQ9 change scoresamong the intervention arms and consider this a clinically meaningful difference in effect. With the alpha error
set at 0.05 and statistical power at 0.80, in order to detect a between-group difference of 1 point (SD = 5) inthe reduction of PHQ9 scores from baseline, we need
522 per group and 1,566 in total for Step II. Assuming a
dropout rate of 10 % and a remission rate of 10 % atweek 3, we need 1,934 participants at Step I.
The sample size required for REPORT #1 was determined as follows. Assuming an intracluster correlation
coefficient to be 0.05 [13, 14], with alpha error at 0.05
and statistical power at 0.80, to detect a difference of 1
point on PHQ9 (SD = 5), that is, to detect an effect size

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Table 1 Reasons for missing data
Reasons for missing data
Week 3

Withdrawal of consent to be assessed
Unable to contact….

Week 9Week 25of 0.2 at week 9, we need 66 patients at each of 30 sites.
We therefore need 1,980 patients at Step I.
Altogether, we concluded that 2,000 patients would beneeded to have enough statistical power to examine ourprimary outcomes for REPORTS #1 and #2.
Datasets to be analyzed

The analyses will be performed according to the intention
to treat (ITT) principle. The ITT population will consistof all randomized subjects regardless of whether he/she
has received the allocated intervention of interest.
Handling of missing data

We will first tabulate the reasons for missing data, compare the baseline characteristics between participants withmissing data versus without missing data, and check thetypes of mechanism of missingness as follows: completely
missing at random, missing at random, and informative
missing (Tables 1 and 2).
Statistical analyses

The draft statistical analysis plan was written by YN, ST
and TAF and was subsequently discussed and approved by

Table 2 Comparison of participants with missing data versus
participants without missing data
Participants withmissing data at
week 3

Participants
without missing
data at week 3

Participants withmissing data at
week 9Participants
without missing
data at week 9

Participants withmissing data at
week 9Participants
without missing
data at week 9Main demographic
and baseline clinicalcharacteristics

Main demographic
and baseline clinicalcharacteristics

Main demographic
and baseline clinicalcharacteristics

Statistics

Yonemoto et al. Trials (2015) 16:459

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Table 3 Protocol deviations
A. Treatment adherence

Total
N (%)

A1. In sertraline 100 mg group, 100 mg not achieved at week 3
A2. In mirtazapine group, sertraline still used (no zero) at week 7.

the Steering Committee. The statistical analyses will be
performed by YN and independently confirmed by ST.
YN will be responsible for all the analyses. We will use
SAS for the analyses.
Patient flow diagram

The flow of participants will be shown in the Consolidated
Standards of Reporting Trials (CONSORT) Flow diagram(Flow diagram for REPORT #1 and REPORT #2).
Protocol deviations

Participants with protocol deviations in eligibility (for example, when a person with an out-of-range age waserroneously registered) will be excluded from the ITT
population, with reasons for exclusion being noted. Thosewith protocol deviations in treatments and/or assessments
will be tabulated (Tables 3 and 4) and will be included in
the ITT analysis.

Demographic and baseline clinical characteristics ofparticipants

Demographic characteristics of all participants will be
described per allocated arm in a table describing thefollowing variables: age, sex (woman or man), education(years), job (employed full-time, employed part-time, on
sick leave, housewife, student or no employment), andmarriage (single, never married; single, divorced or separated; single, deceased; or married). Clinical characteristics to be presented will include the following: age of
onset at first episode, number of previous depressive episodes, length of current episode, out- or inpatient status
at time of entry into the study, PHQ9 at baseline, BDI-IIat baseline, and physical comorbidities.

Table 4 Protocol deviations
Step1

Step2

Step3

Weeks
1 to 3Weeks 3 to 9

Weeks
9 to 2550 mg 100 mg Continue Augment Switch Remitted
sertralineN (%)
B. Treatment deviation
B1. Prohibited concurrent treatments
B2. Impossible to randomize at week 3
B3. No tolerability to sertraline at step 1
B4. Mania at week 1 though week 3
B5. Mania or diagnosis of schizophrenia or dementia at week 3 through 25
C. Stopping intervention and assessment
C1. The participant wishes to stop the protocol treatment.
C2. The trial physician judges that it is difficult to continue the protocoltreatment because of the emergence of serious adverse events (SAE) as
defined below.
C3. The trial physician judges that the risk outweighs the benefit incontinuing the protocol treatment even when no SAE is reported.
C4. The participant becomes pregnant and the trial physician judges thatthe risk outweighs the benefit in continuing the protocol treatment.
C5. The trial physician judges that it is inappropriate to continue theprotocol treatment for any other reason.
D.
D1. The participant withdraws consent to receiving protocol assessments,
regardless of whether he/she is continuing the protocol treatment.
E.
E1. Violation of allowance in timing of assessments of outcomes

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

Yonemoto et al. Trials (2015) 16:459

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Continuous variables will be presented as mean andstandard deviation or, if a considerable skew is present, as
median and interquartile range. The maximum and theminimum of the reported values will also be noted. Binary
and categorical variables will be presented as the numberof participants and percentage. The P values will be calculated for comparisons, if necessary (Tables 5 and 6).
Treatments received

The kinds and amounts of the protocol treatments actually prescribed will be summarized for each intervention
arm at the following time points: week 0; previous dayof weeks 1, 2, 3, 4, 5, 6, 7, 8, and 9 and previous day ofweeks 13, 17, 21 and 25 (Tables 7 and 8).

model-adjusted least-squares means of PHQ-9 at 9
weeks. The model will include the fixed effects of
PHQ-9 score at week 1; all demographic and baseline
clinical variables with statistically significant imbalance between the two arms; treatment (sertraline 50
mg/d versus 100 mg/d); visit and treatment-by-visit
interaction; and clinic/hospital size (whether each site
could be expected to recruit 40 patients or more per
year, a condition used as a stratification variable incluster randomization). The random effect will include the participant and the cluster. Study visit willbe treated as a categorical variable.
The population of interest in this comparison is all
the randomized population under continued/intended
sertraline treatment, including those who haveAnalyses for the primary outcome

For the primary outcome in REPORT #1, we will use
a mixed-model repeated-measures analysis to compare

Table 5 Demographic and baseline clinical characteristics for
REPORT #1
50 mg/d arm
Demographic
Age, mean (SD), min-max
Sex, n (%)
Education n (%)
Junior High school….
Job n (%)
Employed full time….
Marriage n (%)
Single, never married
ClinicalAge of onset at first episode, years,
Number of previous depressive
episodes, N (%)

100 mg/d arm

Table 6 Demographic and baseline characteristics for REPORT #2
Sertraline
Mirtazapine
Mirtazapine
continuation augmentation switch
Demographic
Age, mean (SD)Sex, n (%)
Education n (%)
Junior High school….
Job n (%)
Employed full time….
Marriage n (%)
Single, never married….
ClinicalAge of onset at first
episode, years,
Number of previous
depressive episodes, N (%)

Length of current episode, months

Length of current episode,monthsOut- or inpatient status at time ofentry, N (%)

Out- or inpatient status
at time of entry, N (%)

PHQ9 at time 0,

PHQ9 at time 0,

Mean (SD), range

Mean (SD), range

PHQ9 at baseline,

PHQ9 at baseline,

Mean (SD), range

Mean (SD), range

BDI at baseline,

BDI at baseline,

Mean (SD), range

Mean (SD), range

Physical conditions, N (%)

Physical conditions, N (%)

No physical comorbidity

No physical comorbidity

…..

….

Yonemoto et al. Trials (2015) 16:459

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Table 7 Treatments received for each intervention for REPORT #1
50 mg/d arm

100 mg/d arm

Table 8 Treatments received for each intervention for REPORT#2
Sertralinecontinuation

Week 0Previous day of Week 1
Previous day of Week 2
Previous day of Week 3
Previous day of Week 4
Previous day of Week 5
Previous day of Week 6
Previous day of Week 7
Previous day of Week 8
Previous day of Week 9
Previous day of Week 13

Mirtazapine
augmentation

Mirtazapine
switchPrevious day of Week 4
Previous day of Week 5
Previous day of Week 6
Previous day of Week 7
Previous day of Week 8
Previous day of Week 9
Previous day of Week 13
Previous day of Week 17
Previous day of Week 21
Previous day of Week 25

Previous day of Week 17
Previous day of Week 21
Previous day of Week 25

dropped out of the protocol treatment by week 3,
those who have remitted by week 3 (both of whomwere therefore not randomized for Step II), and one
random third of the remaining patients who havebeen randomized to continue on sertraline for Step II(blue-shaded cells in Fig. 1). In other words, the outcome data will be missing for patients who have been randomized to mirtazapine augmentation or mirtazapine
switching for Step II. We will therefore use inverse probability of censoring weighting to account for the presenceof missing data in parameter estimation for the mixedmodels repeated-measures.
We will present parameters estimated from the model
as well as the effect sizes between the treatments asmean difference (MD) and standardized mean difference(SMD); in order to calculate SMD, SD of the completers’
endpoint scores will be used (Table 9). We will illustrate
the estimated and actual average courses through theacute and continuation treatment phases by interventions (Figure and average course).
For the primary outcome in REPORT #2, we will examine whether the changes in PHQ9 scores from week 3
through week 9 are statistically significantly different
among the sertraline continuation arm, the mirtazapine
augmentation arm and the mirtazapine switch arm. We
will use a mixed-model repeated-measures analysis tocompare model-adjusted least-squares means of PHQ-9 at
9 weeks. The model will include the fixed effects of PHQ-9
score at week 3; treatment (sertraline continuation versus
mirtazapine augmentation versus mirtazapine switch); visit
and treatment-by-visit interaction; stratification variables((i) site, (ii) whether 50 % or greater reduction on PHQ9 isachieved or not, and (iii) whether “moderate” or greater
impairment due to side effects is reported on item 4 of
FIBSER); and the Step I treatment (sertraline 50 mg/d versus 100 mg/d). The random effect will be the participant.
Study visit will be treated as a categorical variable. We will
examine the interaction effect of Step I randomization byadding the Step II treatment by Step I treatment interaction term in the above model.
We will present parameters estimated from themodel as well as the effect sizes between the treatments as mean difference (MD) and standardized
mean difference (SMD): in order to calculate SMD,
SD of the completers’ endpoint scores will be used
(Table 10. ). We will illustrate the estimated andactual average courses through the acute and continuation treatment phases by interventions (Figure andaverage course).

Analyses for the secondary outcomesWe will perform secondary analyses to supplement our
primary analyses and obtain more detailed understandingof our clinical questions. The secondary analyses will use
models similar to those of the primary analyses. We willcalculate mean difference and their 95 % CI for differences
for continuous outcomes and relative risks (RR) and their
95 % CI for dichotomous outcomes.
We will calculate hazard ratios (HR) in Cox regression
and their 95 % CI for differences in continuation of theallocated treatment and of any treatment. Cases who
withdrew consent to assessment and cases lost tofollow-up (for example, moving away) will be censored.
In survival analysis, we will check the assumptions ofproportional hazard (Tables 9 and 10 ) (Figure, Averagecourse and survival curve).

Yonemoto et al. Trials (2015) 16:459

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Table 9 Outcomes for REPORT #1
50 mg/d arm, Mean (SD) n (%)

100 mg/d arm, Mean (SD) n (%)

Difference, RR, HR (95 % CI), P value, and adjusted 1, 2,..

P valuePrimary
Secondary 1
Secondary 2
Secondary 3
Secondary 4…..
Secondary 16
Item 1…
(Subgroup)
XXXX
Primary
Secondary….

Subgroup analyses

For REPORT #1, we will conduct the following a priori
specified subgroup analyses: (i) whether the baseline
PHQ9 score was 15 or more (moderate to severe depression) or not, and (ii) whether the patient had shown
greater or smaller improvement from week 0 to week 1

on sertraline 25 mg/d (split at the median of the observed improvements).
We will analyze subgroups for REPORT #2 according to
the following stratification factors used for randomization
at Step II: (i) whether 50 % or greater reduction on PHQ9
was achieved from week 1 to week 3 or not, and (ii)

Table 10 Outcomes for REPORT #2
Sertralinecontinuation
Primary PHQ9 total score, mean, (SD,
95 % CI)
Effect size
Model-based coefficient, P value
Secondary1 FIBSER total score, mean,(SD, 95 % CI)
Effect size
Model-based coefficient, P value
Secondary 2…
Secondary 16
Item 1 n (%)….
(Subgroup)
XXXX
Primary
Secondary….

Mirtazapine
augmentation

Mirtazapine
switchDifference, RR, HR (95 % CI), Difference Difference
P value, and adjusted 1, 2,

Yonemoto et al. Trials (2015) 16:459

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whether “moderate” or greater impairment due to side effects was reported on item 4 of FIBSER at week 3, as wellas (iii) which treatment arm of Step I the patient was on.

Table 12 Blinding at weeks 9 and 25
ActualGuessContinue
sertraline

Augment

SwitchRemitted

50 mg/day at week 3

Sensitivity analyses

100 mg/day at week 3

For the primary outcomes in REPORTS #1 and #2, wewill conduct the following sensitivity analyses:

Continue sertraline atweeks 9 or 25

1. We will conduct completers’ analyses instead of ITT
analyses.
2. We will conduct the same mixed-model repeatedmeasures analyses but with visit included as acontinuous variable. For this analysis, two models
will be compared in which the visit timing istreated as a linear variable or as a logtransformed variable, and their respective model
fit index will be reported.
3. We will also conduct the same mixed-model
repeated-measures analyses with the actual
assessment timing, not the scheduled assessment
timing, for the above two models. Their respectivemodel fit index will also be reported.
For the primary outcome in REPORT #1 we will further conduct the following sensitivity analyses.
4. For REPORT #1, we will use analysis ofcovariance (ANCOVA) without within-clusteredcorrelation instead of the mixed effect model withwithin-cluster correlations, in order to check theassumption of statistical property by the simpler
analysis, which do not need such assumptions.
5. For REPORT #1, we will conduct the mixed-model
repeated-measures analyses without covariates, thatis, without demographic and baseline clinicalvariables that have shown statistically significant
imbalance between the two arms.
Multiplicity

For each of REPORTS #1 and #2, the significancelevel will be set at P < 0.05. All statistical testing will
Table 11 Blinding at week 3
ActualGuess
50 mg/day at week 3
100 mg/day at week 350 mg/d

100 mg/d

Augment with mirtazapine
at weeks 9 or 25
Switch to mirtazapine atweeks 9 or 25
Remitted at weeks 9 or 25

be two-sided. In REPORT #2, we will compare threearms and will use Hochberg method for adjustmentof multiplicity [15] in the primary analysis. Only
analyses for the primary outcomes have confirmatory
nature and will be controlled for multiplicity. Secondary analyses and secondary outcomes will not be
adjusted for multiplicity, because these analyses have
explanatory and supplemental nature for the primary
analyses.
Evaluation of blinding of outcome assessment

We will calculate kappa coefficients in treatment
guesses for week 3, 9 and 25 assessments in order toascertain the assessors’ blindness to the allocatedtreatments (Tables 11 and 12).
Blind interpretation committee

The statistical analysis report will present the primary
results for REPORTS #1 and #2 without breaking therandomization to the writing committee. The writing
committee will develop interpretations of the results
and associated conclusions assuming for REPORT #1
that Treatment A is the lower dose, and then assuming
Treatment B is the lower dose. Similarly, for REPORT#2, the interpretations will be developed assuming that
Treatment A is any one of the three possibilities, aswith Treatment B and C. These interpretations will berecorded, signed by the participants and made public
on the study web site at that time. The randomization
code will then be broken, the correct interpretation will
be chosen, and the manuscript will be finalized accordingly [16, 17].

Continue sertraline at weeks 9 or 25
Augment with mirtazapine at weeks 9 or 25
Switch to mirtazapine at weeks 9 or 25
Remitted at weeks 9 or 25

Summary of changes from the original protocol

In the original protocol [1], we had specified the following primary and secondary outcomes for each of Steps I
through III.

Yonemoto et al. Trials (2015) 16:459

Page 11 of 13(Continued)
Step I
Patients: Patients with non-psychotic unipolar major depressive episodewho had not received treatment for the index episode before starting
sertraline and who tolerate sertraline at 25 mg/d
Exposure 1: Strategy to titrate sertraline up to the maximum of theeffective range, that is, 25 mg/d ≥ 50 mg/d ≥ 100 mg/d
Exposure 2: Strategy to titrate sertraline up to the minimum of theeffective range, that is, 25 mg/d ≥ 50 mg/d ≥ 50 mg/d

Exposure 1: Strategy to titrate sertraline up to the maximum of theeffective range, that is, 25 mg/d ≥ 50 mg/d ≥ 100 mg/d by week 3, thenallocated to continue sertraline between week 3 and week 9, thentreated at the discretion of the trial physician
Exposure 2: Strategy to titrate sertraline up to the minimum of theeffective range, that is, 25 mg/d ≥ 50 mg/d ≥ 50 mg/d by week 3, thenallocated to continue sertraline between week 3 and week 9, thentreated at the discretion of the trial physician

Outcomes: The primary outcome is the change in PHQ9 scores at week
1 through week 3

Outcome: The primary outcome is the proportion of patients who
continue the allocated treatment up to week 25 and are in remission(4 or less on PHQ9) at week 25

The secondary outcomes include:

The secondary outcomes include:

Change in BDI2 scores at week 1 through week 3

Proportion of patients who continue the allocated treatment up to
week 25 and are showing response (50 % or greater reduction on
PHQ9) at week 25

Proportion of remission (four fewer on PHQ9) at week 3
Proportion of response (50 % or greater reduction on PHQ9) at week 3

Rate of continuation of allocated treatments up to week 25

Proportion of successful continuation of the allocated treatment up to
week 3

Change in PHQ9 at week 1 through week 25

Change in FIBSER at week 1 through week 3

Change in BDI2 at week 1 through week 25

Change in PHQ9 at week 1 through week 9

Suicidality as assessed with C-CASA between week 1 and week 25

Change in BDI2 at week 1 through week 9

Manic/hypomanic/mixed episode between week 1 and week 25

Proportion of remission (four or fewer on PHQ9) at week 9

Serious adverse events between week 1 and week 25

Proportion of response (50 % or greater reduction on PHQ9) at week 9

Step IIIb (exploratory analysis of continuation treatment for Step II)

Proportion of successful continuation of the allocated treatment up to
week 9

Patients: Patients whose major depressive episode did not remit (five or
more on PHQ9) at week 3 to the first-line treatment with sertraline

Change in FIBSER at week 1 through week 9

Exposure 1: Continue sertraline 50 mg/d or 100 mg/d for 6 more weeks,then treated at the discretion of the trial physician

Suicidality as assessed with C-CASA between week 1 and week 9
Manic/hypomanic/mixed episode between week 1 and week 9
Serious adverse events between week 1 and week 9
Step II
Patients: Patients whose major depressive episode did not remit (five or
more on PHQ9) at week 3 to the first-line treatment with sertraline
Exposure 1: Continue sertraline 50 mg/d or 100 mg/d for 6 more weeks
Exposure 2: Augment sertraline with mirtazapine 15 to 45 mg/d
Exposure 3: Switch to mirtazapine 15 to 45 mg/d
Outcome: The primary outcome is the change in PHQ9 at week 4through week 9

Exposure 2: Augment sertraline with mirtazapine 15 to 45 mg/d up to
week 9, then treated at the discretion of the trial physician
Exposure 3: Switch to mirtazapine 15 to 45 mg/d up to week 9, thentreated at the discretion of the trial physician
Outcome: The primary outcome is the proportion of patients who
continue the allocated treatment up to week 25 and are in remission(four or fewer on PHQ9) at week 25
The secondary outcomes include:
Proportion of patients who continue the allocated treatment up to
week 25 and are showing response (50 % or greater reduction on
PHQ9) at week 25
Rate of continuation of allocated treatments up to week 25

The secondary outcomes include:

Change in PHQ9 at week 4 through week 25

Change in BDI2 at week 4 through week 9

Change in BDI2 at week 4 through week 25

Proportion of remission (four or fewer on PHQ9) at week 9

Suicidality as assessed with C-CASA between week 3 and week 25

Proportion of response (50 % or greater reduction on PHQ9) at week 9

Manic/hypomanic/mixed episode between week 3 and week 25

Proportion of successful continuation of the allocated treatment up to
week 9Serious adverse events between week 3 and week 25

Change in FIBSER at week 4 through week 9
Suicidality as assessed with C-CASA between week 3 and week 9
Manic/hypomanic/mixed episode between week 3 and week 9
Serious adverse events between week 3 and week 9
Step IIIa (exploratory analysis of continuation treatment for Step I)
Patients: Patients with nonpsychotic unipolar major depressive episodewho had not received treatment for the index episode before starting
sertraline and who tolerate sertraline 25 mg/d

In this updated protocol, we have merged Step I with
Step IIIa and Step II with Step IIIb into two main reports
in order to present the results of this complex trial in themost clinically informative way. These two reports will
focus on Step I randomization and Step II randomization,
respectively, and both will focus on the acute phase treatment up to 9 weeks as their primary outcome but supplement this with other benefit and harm outcomes for theYonemoto et al. Trials (2015) 16:459

acute phase treatment, as well with benefit and harm outcomes for the continuation treatment up to 25 weeks.
REPORT #1 will examine the clinical questions for
Step I through Step IIIa, as originally postulated in the
published protocol. For this report, however, we havechanged the primary outcome from “Change in PHQ9from 1 through 3 weeks” to “Change in PHQ9 from 1
through 9 weeks” (which was one of the secondary outcomes in the original protocol), in order to fully examine
our clinical question comparing the 50 mg/day arm and100 mg/day arm up to the end of the acute treatment
phase. Week 9 was chosen as the primary outcome
because the acute phase treatment usually is considered
to last 6 to 12 weeks [2, 3]. In order to focus on the effect of the choice of the initial dosage of the first-line
treatment with sertraline through the acute treatment
phase as defined, we will concentrate on those who did
not remit and were subsequently randomized at week 3
to continue on sertraline (hence, a random third of those
who had not remitted by week 3), those who had remitted and were therefore continued on sertraline, andthose who had dropped out of the protocol treatment by
week 3 and subsequently received treatments at physician’s discretion, in order to abide by the ITT principle
for Step I randomization (see blue cells in Fig. 1).
REPORT #2 will deal with the clinical question for
Step II and Step IIIb, as originally postulated in the published protocol, and has set the primary outcome for
Step II as its primary outcome.
The required sample size at Step I remained the samefor REPORT #1 by assuming the same magnitude toeffect to detect at week 9 instead of at week 3. The sample size required at Step II for REPORT #2 also
remained the same; however, we reduced the initial sample size to be recruited into Step I in order to ensure thissample after we reviewed the observed proportion ofpatients who had entered into Step I but subsequently
dropped out of the protocol treatment and could not be
randomized at Step II (from 20 % to 10 %).
All these changes were discussed and agreed upon by
the Steering Committee of the SUN(^_^)D trial before
the randomization code is broken.

Conclusion
This paper presents the updated protocol and the detailed
statistical analysis plan for the SUN(^_^)D trial in order toavoid risks of reporting bias and data-driven results. Dueto the complexity of the trial, we plan to report the main
results of the trial in two reports, and this updated protocol and statistical analysis plan indicate the respective primary and secondary outcomes and their analyses.
Abbreviations
BDI-II: Beck Depression Inventory, 2nd edition; C-CASA: Columbia
Classification Algorithm for Suicide Assessment; FIBSER: Frequency, Intensity

Page 12 of 13

and Burden of Side Effects Rating; PHQ9: Personal Health Questionnaire-9;
PRIME-MD: Primary Care Evaluation of Mental Disorders;SUN(^_^)D: Strategic Use of New Generation Antidepressants for Depression.
Competing interests
NY has received grants or research support from the Japanese Ministry of
Education, Science, and Technology; the Japanese Ministry of Health, Laborand Welfare; and the Japanese Society of Clinical Pharmacology andTherapeutics.
ST has received lecture fees from Kobe City, Astra-Zeneca, Taiho and Ono.
He has received consultation fees from the Pharmaceuticals and Medical
Devices Agency, DeNA Life Science, and CanBus. He has received outsourcing
fees from the Public Health Research Foundation, Japan Breast Cancer ResearchGroup, Satt, and Asahi Kasei Pharma. He has received research funds from theJapanese Ministry of Education, Science, and Technology and the Japanese
Ministry of Health, Labor and Welfare. His wife has been engaged in a research
project of Bayer.
TAF has received lecture fees from Eli Lilly, Meiji, Mochida, MSD, Otsuka,
Pfizer and Tanabe-Mitsubishi, and consultancy fees from Sekisui Chemicals
and Takeda Science Foundation. He has received royalties from Igaku-Shoin,
Seiwa-Shoten and Nihon Bunka Kagaku-sha publishers. He has received grantor research support from the Japanese Ministry of Education, Science, andTechnology, the Japanese Ministry of Health, Labor and Welfare, the Japan
Society for the Promotion of Science, the Japan Foundation for Neuroscienceand Mental Health, Mochida and Tanabe-Mitsubishi.
TK has received lecture fees from Eli Lilly and Tanabe-Mitsubishi, and has
contracted research with GlaxoSmithKline, MSD and Tanabe-Mitsubishi. He
has received royalties from Kyowa Yakuhin and Medical Tribune.
YO has received honoraria for speaking at meetings sponsored by Eli Lilly
and research funds from the Japan Society for the Promotion of Science.
AT has received honoraria for speaking at a meeting sponsored by Eli Lilly
and Tanabe-Mitsubishi.
KM has received speaking fees from Eisai, GlaxoSmithKline, Meiji, MSD,
Otsuka, Pfizer, Lilly, Mochida, Yoshitomi, Dainippon-Sumitomo, Takeda andShionogi.
MI has received lecture fees from Pfizer, Mochida, Shionogi, and Daiichi-Sankyo
outside the submitted work. He has received royalties from Nippon Hyoron
Sha, Nanzando, Seiwa Shoten, Igaku-shoin, and Technomics outside thesubmitted work. He has received grant or research support from the Japanese
Ministry of Health, Labor and Welfare and the Japanese Ministry of Education,
Science, and Technology. The Institution of MI received grant or researchsupport from Eisai, Mochida, Astellas, Otsuka, GlaxoSmithKline, Shionogi,
Sumitomo
Dainippon, Jansen, Pfizer, MSD, Yoshitomi, Daiichi Sankyo, Meiji Seika
Pharma, Tsumura, AbbVie, Ono, and Eli Lilly outside the submitted work.
SS has received lecture fees from Otsuka, MSD, Meiji, Eli Lilly, Mochida, Pfizer,
Takeda Janssen and Tanabe-Mitsubishi. He has received royalties from Sentan
Igaku-sha, Chuohoki, Medical Review publishers. He has received grant or
research support from the Japanese Ministry of Education, Science, andTechnology and the Japanese Ministry of Health, Labor and Welfare.
TA has received speaking fees and/or research funds from Eisai, AstraZeneca, GlaxoSmithKline, Meiji, MSD, Otsuka, Pfizer, Lilly, Mochida, Tanabe,
Yoshitomi, Dainippon-Sumitomo, Takeda, and Shionogi. He has received
royalties from Igaku-Shoin, Nanzando, Chugai-igakusya, Kyorin medical
supply and NHK enterprise. The Japanese Ministry of Education, Science, andTechnology and the Japanese Ministry of Health, Labor and Welfare havefunded his research projects.
MY has received speaking fees from Meiji Seika Pharma and has contracted
research with Nippon Chemiphar.
NW has research funds from the Japanese Ministry of Health Labor andWelfare and the Japanese Ministry of Education, Science, and Technology.
He has also received royalties from Sogensha and Paquet and speaking feesand research funds from Asahi Kasei, Sumitomo Dainippon, Eli Lilly,
GlaxoSmithKline, Janssen, Meiji, MSD, Otsuka and Pfizer.
All the other authors declare that they have no competing interests.
Authors’ contributions
TAF conceived the study. The protocol update was discussed and approved
by NY, TAF, YO, AT, NT, YH, KS, KM, MI, SS, TA, MY and NW. The draft
statistical analysis plan was written by NY, ST and TAF, and was subsequently
critically reviewed, discussed and approved by TK, AM, YO, AT, NT, YH, KS,

Yonemoto et al. Trials (2015) 16:459

KM, MI, SS, TA, MY, NW and GHG. All authors read and approved the final
manuscript.

Acknowledgments
This trial was funded by a Grant-in-Aid from the Ministry of Health, Laborand Welfare, Japan (H22-Seishin-Ippan-008) (from April 2010 to March 2012)and by a research project “Pragmatic Psychopharmacotherapy Research” of
the Japan Foundation for Neuroscience and Mental Health (from April 2012
to present).
Author details
Department of Neuropsychopharmacology, National Institute of Mental
Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi,
Kodaira, Tokyo 187-8553, Japan. 2Leuven Biostatistics and Statistical
Bioinformatics Center, Katholic University of Leuven, Kapucijnenvoer 35, 3000
Leuven, Belgium. 3Department of Pharmacoepidemiology, Kyoto University
Graduate School of Medicine/of Public Health, Yoshida Konoe-cho, Sakyo-ku,
Kyoto 606-8501, Japan. 4Department of Health Promotion and Human
Behavior, Kyoto University Graduate School of Medicine/School of Public
Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. 5Department ofClinical Epidemiology, Kyoto University Graduate School of Medicine/Schoolof Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
6
Aratama Mental Clinic, 1-49 Suyama-cho, Mizuho-ku, Nagoya 467-0066,
Japan. 7Mantani Mental Clinic, 5-18 Itsukaichi Ekimae 1-chome, Saeki-ku,
Hiroshima 731-5125, Japan. 8Miki Mental Clinic, 1-3 Hiranuma 1-chome,
Nishi-ku, Yokohama 220-0023, Japan. 9Department of Neuropsychiatry,
Okayama University Hospital, 2-5-1, Shikata-cho, Kita-ku, Okayama 700-8558,
Japan. 10Department of Neuropsychiatry, Kochi Medical School, Kohasu,
Okoh-cho, Nankoku 783-8505, Japan. 11Department of Psychiatry andCognitive-Behavioral Medicine, Nagoya City University Graduate School of
Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
12
Translational Medical Center, National Center of Mental Health, National
Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo
187-8502, Japan. 13Department of Clinical Epidemiology and Biostatistics,
McMaster University, West Hamilton, Ontario L8N 3Z5, Canada.
1

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Received: 15 June 2015 Accepted: 30 September 2015

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