2. TITLE
➤ Acceptability of escitalopram versus duloxetine in outpatients with depression who
did not respond to initial second-generation antidepressants: A randomized, parallel-
group, non-inferiority trial
➤ Authors: Kazuyuki Nakagome, MD, PhD , Yuma Yokoi, MD, PhD , Atsuo
Nakagawa, MD, PhD , Masayuki Tani, MD, PhD , Gentaro Nishioka, MD, PhD , Naoki
Yoshimura, MD, PhD , Toshiaki A. Furukawa, MD, PhD , Koichiro Watanabe, MD,
PhD , Masaru Mimura, MD, PhD , Akira Iwanami, MD, PhD , Takayuki Abe, PhD
3. AIM OF THE STUDY
➤ To test the hypothesis that escitalopram is non-inferior in acceptability to duloxetine
as a second-line treatment among patients with MDD.
➤ To explore the long-term effect of drug selection as a second-line treatment on
acceptability involving switching to the other drug.
4. METHODOLOGY
➤ Study design: Randomised, flexible-dose, parallel-group, multi-center trial
➤ Duration: December 2013 to March 2017
➤ Site: Japan
➤ Sample size: 161
➤ Sample selection: Stratified block randomisation strategy
➤ Inclusion criteria:
1.Patients diagnosed as MDD according to DSM-IV criteria using M.I.N. I. with no history of
bipolar disorder, schizophrenia, or other psychotic disorders
2.Age between 20 and 65 years.
3.Patients who have been treated with a therapeutic dose of only one SSRI, SNRI or
mirtazapine for at least 3 weeks without optimal response defined by Clinical Global
Impression of Severity (CGI-S) score of ≥ 4
5. METHODOLOGY
➤ Exclusion criteria
➤ Patients who did not respond to two or more adequate antidepres- sants, each lasting for more than 4 weeks, during
the current depressive episode
➤ Patients who did not respond to escitalopram or duloxetine at the maximum dose for at least 4 weeks during the
previous depressive episode.
➤ Patients with history of substance abuse/dependence within one year of screening, except caffeine and nicotine
➤ Women who are currently pregnant or breast feeding
➤ Patients at serious risk of harm to themselves or others
➤ Patients who have serious and/or unstable illness
➤ Patients who have a serious or unstable cardiovascular illness (including severe arrhythmia with bradycardia,
prescribed drugs known to cause QTc prolongation, congestive heart failure, and hypokalemia) or a clinically
significant ECG abnormality (male: QTc>450 ms, female: QTc>470 ms)
➤ Patients who are treated with pimozide at the screening or monoamine oxidase inhibitors within 2 weeks before the
screening,
6. ➤ Recruitment: Two university hospitals ( Keio and Showa Universities) along with their
branch hospitals and clinics, and National Center of Neurology and Psychiatry (NCNP)
➤ Ethical committee approval- obtained
➤ Assessment: At the baseline (within 2 weeks from screening)
➤ Severity of depression by 16 items Quick Inventory of Depressive Symptomatology –
Self-Reported (QIDS-SR16) and CGI-S
➤ Quality of life by European Quality of Life Questionnaire-5 Dimension (EQ-5D)
➤ Central raters blinded to the treatment allocation evaluated depression severity by
Patient Healthcare Questionnaire – 9 (PHQ-9) and functional impairment level by the
Sheehan Disability Scale (SDS)
7.
8. PRIMARY OUTCOME MEASURES
➤ Rate of discontinuation for any reason at 8weeks
➤ 1 Intolerance (by the scores of FIBSER (Frequency, Intensity, and Burden of Side
Effects Rating))
➤ 2 Voluntarily (complaints from the patient’s side)
➤ 3 Worsening of symptoms (CGI-I score ≥6 in two consecutive visits-)
➤ 4 Withdrawal of consent
➤ 5. Other safety issues( gestation, accidents)
➤ 6 Unable to continue treatment( inevitable reasons )
➤ 7 Other reasons
9. SECONDARY OUTCOME MEASURES
➤ Rate of discontinuation at week 16 and 52
➤ Efficacy
➤ Change in the severity of depression at week 8, 16 and 52 (PHQ-9, CGI-S, and
QIDS-SR)
➤ The proportion of responders at week 8, 16 And 52 ( 50% or greater reduction
from the baseline PHQ-9 score)
➤ The proportion of remitters at week 8, 16 and 52 (PHQ-9 score ≤4)
10. ➤ Health outcomes:
1 Change in quality of life (EQ-5D at week 8, 16 and 52 )
2 Change in functional impairment measures (SDS at week 8, 16 and 52)
➤ Safety:
1 The global burden of side effects (FIBSER Scale at week 8, 16 and 52 )
2 Adverse Events (AEs) and Serious Adverse Events (SAEs)
3 Electrocardiography and blood tests as needed.
11. STATISTICAL ANALYSIS- PRIMARY ANALYSIS
➤ Primary analysis population in this trial is intention-to-treat (ITT)
➤ The primary endpoint is the proportion of discontinuation of the allocated treatment
for any reason at week 8.
➤ The non-inferiority of escitalopram to duloxetine will be tested using the one-sided
95% confidence interval (CI) for the between-group difference in the proportion of
discontinuation (escitalopram− duloxetine).
➤ If the upper limit of the one-sided 95% CI was less than the non-inferiority margin (Δ
= 10%), escitalopram was considered to be non-inferior to duloxetine.
12. SECONDARY ANALYSIS
➤ The proportion of discontinuation of the trial for any reason at week 16 and 52 were
compared using the two-sided 95% Wald CI
➤ Mixed-effects model for repeated measurements (MMRM)- compare mean changes
from the baseline between the two groups
➤ Degrees of freedom for errors were adjusted with the Kenward-Roger method
➤ 95% CI for response rate, remission rate was estimated using the Clopper Pearson
method, and proportions were compared with chi-squared test
➤ Change from baseline in ordinal variables (CGI-S, SDS) by one sample Wilcoxon
signed-rank test and between-group differences were tested using Wilcoxon rank-sum
test
➤ Kaplan-Meier method was used for analysis with time-to-event data
15. PRIMARY ENDPOINT
➤ The primary endpoint of non-inferiority of escitalopram to duloxetine in
discontinuation rate at week 8 was established as the one-sided 95% upper
confidence limit fell below the non-inferiority margin of 0.10 and escitalopram
(4.9%)was significantly below duloxetine (19.2%) in discontinuation rate
16. SECONDARY ENDPOINTS
➤ In terms of the discontinuation rate at week 16 and 52, Group A (9.8%) was
significantly below Group B (26.9%) at week 16, whereas at week 52 the between-
group difference (Group A: 31.7%; Group B: 43.6%) was no longer significant
➤ No significant difference between groups in the measures’ change from the baseline
at any timepoint
➤ No significant difference between the allocated treatment groups in either response
or remission rate at any timepoint
➤ No significant difference between the allocated treatment groups in any FIBSER
score at any timepoint
17. LIMITATIONS
➤ First, the withdrawal of consent was the major reason for the discontinuation in Group B, which was
different from Group A. Although we acknowledge this is based on the patient’s intent, we could have better
asked for more concrete reason for the withdrawal of consent from the perspectives of the patients.
➤ Second, from Step 2 the medication had been switched to the other drug in some patients and thus, the
outcome could not be attributed to acceptability of drugs per se.
➤ Thirdly, we adopted a stratified block randomization per center , concealment of allocation was not assured
beforehand, which may have caused a selection bias.
➤ Fourthly, the drug switching scheme was not specified in the study, which might have influenced the
occurrence of adverse effects.
➤ Fifthly, the patients who discontinued due to clear intolerance (n = 4) or clinical worsening (n = 1) during
Step 1 dropped out of the study, which removed those patients from Step 2 causing potential selection bias
in findings regarding Step 2.
➤ Finally, the change of the primary endpoint during the trial may have caused potential bias to the
discontinuation rate.
18. FUNDING
➤ Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd. and the
Japan Foundation for Neuroscience and Mental Health
19. CRITICAL APPRAISAL
➤ Title-Identified as a randomised trial in the title
➤ Abstract- Structured summary of trial design, methods, results, and
conclusions are given
➤ Background- Scientific background and explanation of rationale are given
➤ Objectives- Specific objectives or hypotheses are given
➤ Trial design- Description of trial design (such as parallel, factorial) including
allocation ratio was done
➤ Changes to trial design- Change in the primary endpoint in initial protocol has
been done with explained reason
20. ➤ Participants- Comprehensive description of the eligibility criteria is given
➤ Study settings- Described the Settings and locations where the data were
collected
➤ Interventions- The interventions for each group with sufficient details to allow
replication, including how and when they were actually administered - not fully
explained
➤ Outcomes- Completely defined pre-specified primary and secondary outcome
measures, including how and when they were assessed
➤ Changes to outcome- Change in the primary endpoint in initial protocol has
been done with explained reason
21. ➤ Sample size- Determination of sample size is explained
➤ Interim analysis- explanation is not given
➤ Randomisation- Method used to generate the random allocation sequence is
given
➤ Type of randomisation- Given
➤ Randomisation: Allocation concealment mechanism- not done
➤ Randomisation: Implementations- not explained
➤ Blinding- Analyst was blinded
➤ Similarity of interventions- not done
22. ➤ Statistical methods- Statistical methods used to compare groups for primary
and secondary outcomes are explained
➤ Additional analysis- Not done
➤ Results: Participant flow: For each group, the numbers of participants who
were randomly assigned, received intended treatment, and were analysed for
the primary outcome
➤ Losses and exclusions- For each group, losses and exclusions after
randomisation, together with reasons are given
➤ Recruitment-Dates defining the periods of recruitment and follow-up are not
given
23. ➤ Reason for stopped trial- not applicable
➤ Baseline data- A table showing baseline demographic and clinical
characteristics for each group is given
➤ Numbers analysed- For each group, number of participants (denominator)
included in each analysis and the analysis was by original assigned groups
➤ Outcomes and estimation- For each primary and secondary outcome, results
for each group, and the estimated effect size and its precision (such as 95%
confidence interval) are given
➤ Binary outcomes- Response rate and remission rate are estimated using the
Clopper Pearson method
24. ➤ Ancillary analysis- Not applicable
➤ Harms- All important harms or unintended effects in each group are explained
➤ Discussion: Limitations-Trial limitations, addressing sources of potential bias,
imprecision are given
➤ Generalisability- questionable
➤ Interpretation- Interpretation consistent with results, balancing benefits and harms,
and considering other relevant evidence
➤ Registration- Registration number and name of trial registry are not given
➤ Protocol- Where the full trial protocol can be accessed is given
➤ Funding- Sources of funding and other support (such as supply of drugs), role of
funders are given
