Atkinson 2014.

Study characteristics
Methods	Trial design: Double‐blind randomised placebo‐controlled trial. Three parallel groups. 65 sites Power calculation: Based on an anticipated enrolment of 336 patients, randomised in a 1:1:1 ratio across the three groups. Assumed approximately 10% dropout, leaving approximately 100 patients per treatment arm post‐baseline. Estimated 80% power to detect an effect size of 0.40 (duloxetine efficacy relative to placebo on the CDRS‐R total score) using a two group t‐test with a 0.05 two‐sided significance level. The effect size of 0.4 was determined based on historical data for the effect size of duloxetine 60 mg QD in adult patients with MDD. Use of diagnostic criteria (or clear specification of inclusion criteria): Yes. MDD without psychotic features, single or recurrent episode, as defined by DSM‐IV‐TR. MDD diagnosis was supported by the Mini International Neurospychiatric Interview for children and adolescents (MINI‐KID). Intervention integrity: Not described Outcome measures described or validated measures used: Yes. Children’s Depression Rating Scale‐Revised (CDRS‐R). Follow‐up assessment points: Weeks 1, 2, 4, 7, and 10 during the placebo‐controlled acute treatment period, and at weeks 12, 14, 16, 20, 24, 28, 32, and 36 during the double‐blind long‐term treatment period No. crossed: None Funded by: Eli Lilly and Company
Participants	Setting of care: Outpatient Recruitment: Not described Mean age (SD): Duloxetine = 13.1 (3.0) Fluoxetine = 13.1 (3.3) Placebo = 13.3 (3.1) Age range: 12 – 17 Gender (F:M) Duloxetine = 64:53 Fluoxetine = 61:56 Placebo = 51:52 Methods used to diagnose: MDD without psychotic features, single or recurrent episode, as defined by DSM‐IV‐TR. MDD diagnosis was supported by the Mini International Neurospychiatric Interview for children and adolescents (MINI‐KID). Conducted by two independent evaluators, with at least one evaluator being a psychiatrist Diagnosis: MDD Baseline severity of depression: (Note: The SDs were incorrectly reported in the primary paper as SEs) CDRS‐R total score, Mean (SD) Duloxetine = 59.2 (10.5) Fluoxetine = 58.8 (10.6) Placebo = 60.2 (11.7) CGI‐Severity score, Mean (SD) Duloxetine = 4.5 (0.6) Fluoxetine = 4.5 (0.6) Placebo = 4.6 (0.7) Length of current episode: Not reported. % first episode: 71.5% Comorbidity (intervention): Not reported, however those with significant suicidal risk, comorbid psychiatric conditions requiring medication to manage, or other significant or unstable medical conditions, were excluded. Comorbidity (control): Not reported, however those with significant suicidal risk, comorbid psychiatric conditions requiring medication to manage, or other significant or unstable medical conditions, were excluded. Location: 65 psychiatric clinical sites in nine countries (United States, Finland, France, Germany, Slovakia, Estonia, Russia, Ukraine, and South Africa) Subjects enrolled per country: United States: 140 Finland: 5 France: 8 Germany: 4 Slovakia: 6 Ukraine: 66 Russian Federation: 40 Estonia: 1 South Africa: 67 Inclusion criteria: · Outpatient, diagnosed with major depressive disorder (MDD) as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM‐IV‐TR) and supported by the Mini International Neuropsychiatric Interview for children and adolescents (MINI‐KID) · Diagnosis of moderate or greater severity of MDD as determined by Children's Depression Rating Scale ‐ Revised (CDRS‐R) with a total score greater than or equal to 40 at screen, and randomisation and a Clinical Global Impression of Severity (CGI‐Severity) rating of greater than or equal to 4 at screen, and randomisation · Female patients must test negative for pregnancy during screening. · Judged to be reliable by the investigator to keep all appointments for clinical visits, tests, and procedures required by the protocol · Has a degree of understanding such that they can communicate intelligently with the investigator and study coordinator · Capable of swallowing study drug whole · Patients must have venous access sufficient to allow blood sampling and are compliant with blood draws as per the protocol. Exclusion criteria: · Children of site personnel directly affiliated with this study and/or their immediate families · Children of Lilly employees or employees of the designated clinical research organisation (CRO) assisting with the conduct of the study · Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry · Have a current or previous diagnosis of bipolar disorder, psychotic depression, schizophrenia or other psychotic disorder, anorexia, bulimia, obsessive compulsive disorder, or pervasive development disorder, as judged by the investigator · Have a history of DSM‐IV‐TR‐defined substance abuse or dependence within the past year, excluding caffeine and nicotine · Have a current primary DSM‐IV‐TR Axis I disorder other than MDD or a current secondary DSM‐IV‐TR Axis I disorder that requires any pharmacologic treatment · Have 1 or more first‐degree relatives with diagnosed bipolar I disorder · Have a significant suicide attempt within 1 year of screening or are currently at risk of suicide in the opinion of the investigator · Have a weight less than 20 kilogram (kg) at screening · Have a lack of response to 2 or more adequate treatment trials of antidepressants at a clinically appropriate dose for a minimum of 4 weeks for the same MDD episode · Have initiated, stopped, or changed the type or intensity of psychotherapy within 6 weeks prior to screening · Have a history of seizure disorder (other than febrile seizures) · Have a history of electroconvulsive therapy within 1 year of screening · Have had treatment with a monoamine oxidase inhibitor (MAOI) within 14 days or fluoxetine within 30 days of randomisation; or the potential need to use an MAOI during the study or within 5 weeks of discontinuation of study drug · Have previously enrolled, completed, or withdrawn from this study or any other study investigating duloxetine or fluoxetine · Have a positive urine drug screen for any substances of abuse or excluded medication · Are taking any excluded medications that cannot be discontinued by screening · Have known hypersensitivity to duloxetine, fluoxetine, or their inactive ingredients; or have frequent or severe allergic reactions to multiple medications · Have uncontrolled narrow‐angle glaucoma · Have acute liver injury or severe cirrhosis · Have a serious or unstable medical illness, psychological condition, or clinically significant laboratory or electrocardiogram (ECG) result that, in the opinion of the investigator, would compromise participation in the study or be likely to lead to hospitalisation · Have abnormal thyroid‐stimulating hormone concentration · Have initiated or discontinued hormone therapy within the previous 3 months · Female patients who are either pregnant, nursing or have recently given birth · Need to use thioridazine during the study or within 5 weeks after discontinuation of study drug or need to use pimozide during the study Exclusion of suicidality: Have a significant suicide attempt within 1 year of screening or are currently at risk of suicide in the opinion of the investigator
Interventions	Intervention group 1: Drug: duloxetine Dosage: 60–120 mg per day Regimen: 30 mg per day for 2 weeks, increased to 60 mg per day at the 2‐week time point. Could be increased to 90 mg per day at the 4‐week time point or later, and subsequently increased to 120 mg per day at the 7‐week time point or later. Lowest dose allowed after the 2‐week time point was 60 mg per day. Length of treatment: 10 weeks Intervention group 2: Drug: fluoxetine Dosage: 20–40 mg per day Regimen: 10 mg per day for 2 weeks, increased to 20 mg per day at the 2‐week time point. Could be increased to 40 mg per day at the 4‐week time point or at any later time point. Lowest dose allowed after the 2‐week time point was 20 mg per day. Length of treatment: 10 weeks Control group: Patients randomised to placebo remained on placebo throughout the 10‐week acute treatment period.
Outcomes	Definition and assessment of response: Primary outcome was change from baseline in Children's Depression Rating Scale‐Revised (CDRS‐R) total score at week‐10 endpoint. Depressive symptoms: Children’s Depression Rating Scale–Revised (CDRS‐R) Functioning: Not assessed Suicidal behaviour: Columbia‐Suicide Severity Rating Scale (C‐SSRS) Other measures: Clinical Global Impressions (CGI)‐Severity
Notes	Type of data used for remission/response: Intention‐to‐treat
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	No statement. “Patients meeting entry criteria were randomly assigned 1:1:1 to either duloxetine flexible dose (60–120 mg once daily [QD]), fluoxetine flexible dose (20–40 mg QD), or placebo, via Interactive Voice Response System (IVRS).” pg.181. Stratified randomisation by age: children (7‐11 years) and adolescents (12‐17 years). FDA statistical review. Comment: Likely implemented adequate random sequence generation given use of IVRS, no baseline imbalance of major concern, however no statement reported
Allocation concealment (selection bias)	Low risk	Patients meeting entry criteria were randomly assigned 1:1:1 to either duloxetine flexible dose (60–120 mg once daily [QD]), fluoxetine flexible dose (20–40 mg QD), or placebo, via Interactive Voice Response System (IVRS). pg.181 Atkinson 2014
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Trial registry entry (NCT00849901) stated “Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)” “double‐blind” “…because of the need to blind multiple doses of two different drugs, all patients were required to take six capsules of study drug per day” pg.188 Atkinson 2014. Comment: likely adequate blinding of participants and personnel, although no statement on how blinding was maintained or evaluated and differential dropout due to adverse events
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Trial registry entry (NCT00849901) stated “Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)”. Comment: likely outcome assessor was blind, however no statement in Atkinson 2014, and differential dropout due to adverse events
Incomplete outcome data (attrition bias) All outcomes	Low risk	Number eligible: not reported, 438 patients screened Number randomised: 337; duloxetine: 117; fluoxetine: 117; placebo: 103 Number started trial: 337; duloxetine: 117; fluoxetine: 117; placebo: 103 Number of withdrawals: 72; duloxetine: 30; fluoxetine: 26; placebo: 16 Number analysed post‐intervention: 329; duloxetine: 113; fluoxetine: 113; placebo: 103 Reasons for dropout: Adverse events: duloxetine = 9; fluoxetine = 1; placebo = 3 Lack of efficacy: duloxetine = 2; fluoxetine = 3; placebo = 2 Physician decision: duloxetine = 1; fluoxetine = 1; placebo = 1 Parent/carer decision: duloxetine = 11; fluoxetine = 5; placebo = 4 Patient decision: duloxetine = 4; fluoxetine = 10; placebo = 4 Lost to follow‐up: duloxetine = 2; fluoxetine = 4; placebo = 1 Sponsor decision: duloxetine = 1; fluoxetine = 0; placebo = 0 Protocol violation: duloxetine = 0; fluoxetine = 2; placebo = 1 Comment: differential dropout rate, duloxetine = 25.6%, fluoxetine = 22.2%, placebo = 15.5%. Dropout due to adverse events and parent/carer decision higher in duloxetine, patient withdrawal higher in fluoxetine. ITT analysis: modified ITT population included all randomised patients with both a baseline and at least one post‐baseline value for CDRS‐R (corresponded to 329 patients) pg.182 Atkinson 2014. Statistical analysis: using the ITT population, the primary efficacy parameter of (LS) mean change from baseline on the CDRS‐R was estimated using the restricted maximum likelihood (REML)‐based mixed‐effects model for repeated measure (MMRM). All available observations from each post‐baseline visit were included (OC). The MMRM model included the fixed categorical effects of treatment, pooled investigative site, visit, treatment‐by‐visit interaction, age category, and age category‐by‐visit interaction, as well as the continuous, fixed covariates of the baseline CDRS‐R, and the baseline CDRS‐R‐by‐visit interaction. An unstructured covariance structure was used to model the within‐patient errors. A Kenward–Roger correction was used to estimate denominator degrees of freedom. Significance tests were based on least‐squares means (LS means) using a two‐sided ⍶ = 0.05. Additional analyses are reported using ANOVA and ANCOVA (baseline CDRS‐R, age category as covariates) models with LOCF approach. Secondary outcomes of CDRS‐R response and remission were estimated as probabilities using a categorical MMRM approach, in which a marginal model based on a pseudolikelihood method was utilised and implemented in SAS PROC GLIMMIX. Model included the fixed categorical effects of treatment, pooled investigative site, visit, treatment‐by‐visit interaction, age category, and age category‐by‐visit interaction, as well as the continuous, fixed covariates of the baseline CDRS‐R, and the baseline CDRS‐R‐by‐visit interaction.
Selective reporting (reporting bias)	Unclear risk	All outcomes in methods reported? Yes Data available for use in MA? Yes Note: Atkinson 2014 reported change from baseline scores for CDRS‐R but no standard errors. These are fully reported in the trial registry entry (NCT00849901). CDRS‐R “probabilities” of response and remission are reported as percentages only, without events or denominators. pg.185 Atkinson 2018. Clinical trials registry entry but no access to protocol. Atkinson 2014 pg.181 stated the protocol was filed with United States FDA prior to study initiation. Protocol and Statistical Analysis Plan have not been published. Available sources are trial registry entry (NCT00849901), F1J‐MC‐HMCK clinical study report synopsis and FDA statistical review.
Other bias	Unclear risk	Contact: clinic visits scheduled weekly during screening and at weeks 1, 2, 4, 7, 10 (acute phase endpoint) Screening: weekly, 2‐4 weeks prior to baseline. “Participants met DSM‐IV‐TR criteria for MDD without psychotic features, had a CDRS‐R total score >/= 40 and a CGI‐S score >/= 4 at the three screening visits” pg.181. Placebo lead‐in: no statement Baseline imbalance: “There were no significant between‐group differences in baseline demographics or psychiatric profile (Table 1).” pg.183 Atkinson, however supporting analysis not reported. Baseline CDRS, CGI‐S, age, sex, BMI, race, and ethnicity appear balanced. Other potentially important covariates (e.g. comorbidities) not reported