# Abstract

 # Abstract

 ***Objectives:*** To evaluate the short-term efficacy and safety of desvenlafaxine (25--50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). ***Methods:*** Outpatient children (7--11 years) and adolescents (12--17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale--Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions--Severity, Clinical Global Impressions--Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. ***Results:*** The safety population included 339 patients (children, *n* = 130; adolescents, *n* = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, −22.6 [1.17]) or fluoxetine (−24.8 [1.17]; placebo, −23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; *p* = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). ***Conclusion:*** Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25--50 mg/d was generally safe and well tolerated in children and adolescents in this study. # Results 

## Study population A total of 340 patients were randomly assigned to treatment; 339 patients (children, *n* = 130; adolescents, *n* = 209) were included in the safety population (desvenlafaxine, *n* = 115; fluoxetine, *n* = 112; placebo, *n* = 112). The ITT population included 130 children and 207 adolescents. A total of 42 (12%) patients discontinued early (desvenlafaxine, 16 [14%]; fluoxetine, 13 [12%]; and placebo, 13 [12%]). Lost to follow-up was the most common reason for discontinuation from the desvenlafaxine and placebo groups; in the fluoxetine group, the most common reason for discontinuation was "no longer willing to participate" ([Fig. 1](#)). <figure> <p><img src="" /></p> <figcaption>Study flow. <sup>a</sup>One patient was screened and, although not randomized, received a total of eight blinded placebo doses. The patient was discontinued after the week 1 visit once the error was identified and listed as a protocol violation.</figcaption> </figure> Demographic and baseline characteristics were comparable among treatment groups for both children and adolescents ([Table 1](#)). Mean (SD) CDRS-R Total Score at baseline was 56.5 (8.9), mean (SD) CGI-S score was 4.5 (0.6), and the duration of the most recent depressive episode ranged from 1 to 96 months (median, 7; mean [SD], 13.4 [15.1]). Overall, 30.4% (103) of patients in the safety population had a prior or active psychiatric condition other than MDD in their medical history (desvenlafaxine, 31.3%; fluoxetine, 25.9%; and placebo, 33.9%). The most common psychiatric conditions (reported by ≥2% of patients) included attention-deficit/hyperactivity disorder (desvenlafaxine, 12.2%; fluoxetine, 13.4%; and placebo, 5.4%), nonsuicidal self-injurious behavior (desvenlafaxine, 7.0%; fluoxetine, 8.0%; and placebo, 12.5%), insomnia (desvenlafaxine, 7.0%; fluoxetine, 6.3%; and placebo, 8.0%), generalized anxiety disorder (desvenlafaxine, 0.9%; fluoxetine, 6.3%; and placebo, 0), and oppositional defiant disorder (desvenlafaxine, 3.5%; fluoxetine, 3.6%; and placebo, 0). ::::table-wrap

::: caption
\[Demographic and Baseline Characteristics, Safety
Population\]{.smallcaps}
:::

*Children* *Adolescents*

______________________________________________________________________

*Placebo (*n* = 42)* *Fluoxetine (*n* = 45)* *Desvenlafaxine (*n* = 43)* *Total (*n* = 130)* *Placebo (*n* = 70)* *Fluoxetine (*n* = 67)* *Desvenlafaxine (*n* = 72)* *Total (*n* = 209)*
Age, mean (SD), years 9.4 (1.3) 9.6 (1.3) 9.3 (1.4) 9.4 (1.3) 14.6 (1.5) 14.7 (1.6) 15.0 (1.5) 14.8 (1.5)
Sex, *n* (%)\
Female 23 (55) 14 (31) 20 (47) 57 (44) 41 (59) 43 (64) 43 (60) 127 (61)
Male 19 (45) 31 (69) 23 (53) 73 (56) 29 (41) 24 (36) 29 (40) 82 (39)
Race, *n* (%)\
Asian 1 (2) 0 1 (2) 2 (2) 0 2 (3) 0 2 (1)
Black 15 (36) 15 (33) 14 (33) 44 (34) 10 (14) 19 (28) 18 (25) 47 (22)
White 25 (60) 26 (58) 23 (53) 74 (57) 56 (80) 41 (61) 49 (68) 146 (70)
Other 1 (2) 4 (9) 5 (12) 10 (8) 4 (6) 5 (7) 5 (7) 14 (7)
Height, mean (SD), cm 140.5 (10.6) 141.3 (11.2) 144.3 (11.5) 142.0 (11.1) 164.5 (9.8) 165.8 (8.4) 167.3 (9.1) 165.9 (9.2)
Weight, mean (SD), kg 39.4 (14.0) 44.0 (18.9) 46.0 (15.2) 43.2 (16.3) 68.0 (19.1) 73.3 (21.8) 71.7 (19.0) 71.0 (20.0)
BMI, mean (SD), kg/m^2^ 19.5 (4.7) 21.3 (6.4) 21.6 (5.0) 20.8 (5.5) 25.0 (6.0) 26.5 (6.9) 25.5 (5.8) 25.6 (6.3)
Duration of most recent episode, median (range), months 11 (1--57) 6 (1--42) 8 (1--71) 7 (1--71) 8 (1--69) 7 (1--96) 7 (1--61) 7 (1--96)
CDRS-R total score, mean (SD) 57.0 (8.6) 55.0 (8.7) 56.4 (10.9) 56.1 (9.4) 57.1 (9.1) 57.0 (8.1) 56.3 (8.8) 56.8 (8.7)

BMI, body mass index; CDRS-R, Children's Depression Rating
Scale--Revised; SD, standard deviation.:::: 

## Efficacy Statistical separation from placebo was not observed on the primary efficacy endpoint for either desvenlafaxine or for the fluoxetine reference group. Adjusted mean (standard error) change from baseline in CDRS-R total score at week 8 was −22.6 (1.17) and −23.1 (1.18) for the desvenlafaxine and placebo groups, respectively, and for fluoxetine was −24.8 (1.17) ([Fig. 2](#)). The change from baseline in CDRS-R over the 8-week treatment phase was similar for the three arms. Point differences were statistically significant between desvenlafaxine and placebo at week 2 and between fluoxetine and placebo at weeks 1 and 2; no significant differences were observed at any other time points. Results were similar for the child and adolescent groups in an exploratory analysis of change from baseline in CDRS-R total score ([Supplementary Fig. S1](#)). <figure> <p><img src="" /></p> <figcaption>Adjusted mean (SE) change from baseline in CDRS-R total score in children and adolescents; MMRM analysis, ITT population. \*<em>p</em> \< 0.01, fluoxetine versus placebo. <sup>†</sup><em>p</em> \< 0.05, fluoxetine versus placebo and desvenlafaxine versus placebo. CDRS-R, Children's Depression Rating Scale–Revised; CI, confidence interval; ITT, intent-to-treat; MMRM, mixed-effects model for repeated measures; SE, standard error.</figcaption> </figure> At week 8, the CGI-I response rate for fluoxetine (78.2%) was significantly greater compared with placebo (62.6%; *p* = 0.017). Week 8 CGI-I response rate for desvenlafaxine (68.7%) was also greater than placebo, although this comparison did not reach statistical significance (*p* = 0.343). Results for CGI-S and CGI-I scores were otherwise consistent with those for CDRS-R total score, with no statistically significant difference from placebo for either desvenlafaxine or fluoxetine at week 8 ([Table 2](#)). ::::table-wrap
::: caption
[Summary of Secondary Efficacy Outcomes at Week 8]{.smallcaps}
:::

*CGI-S* n *Adjusted mean change (SE) from baseline*^[a](#)^ *Difference in adjusted means (placebo-active)* *95% CI* p

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Placebo 99 −1.71 (0.12) --- --- ---
Fluoxetine 101 −1.88 (0.12) 0.18 −0.11 to 0.46 0.224
Desvenlafaxine 99 −1.70 (0.11) −0.01 −0.29 to 0.27 0.944

*CGI-I*^[b](#)^ n *Very much improved (%)* *Much improved (%)* *Minimally improved (%)* *No change (%)* *CMH test*^[c](#)^ p\*-value\*

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Placebo 99 27.3 35.4 32.3 4.0 ---
Fluoxetine 101 30.7 47.5 16.8 4.0 0.095
Desvenlafaxine 99 23.2 45.5 21.2 9.1 0.852

*CGI-I response*^[d](#)^ *Proportion responders* *%* *Adjusted odds ratio*^[e](#)^ *Wald 95% CI* p

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Placebo 62/99 62.6 --- --- ---
Fluoxetine 79/101 78.2 0.465 0.249 to 0.871 0.017
Desvenlafaxine 68/99 68.7 0.751 0.415 to 1.357 0.343

Estimates of adjusted mean, SE, difference in means, 95% CI, and
*p*-values were based on a mixed-effects model for repeated measures for
the change from baseline in CGI-S with terms for treatment, week,
interaction of treatment and week, age group, country, gender, and
baseline CGI-S total score.

CGI-I scored as 1, very much improved; 2, much improved; 3, minimally
improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much
worse. No patients scored 5--7 at week 8.

CMH test was controlled for age group and country.

CGI-I response was defined as CGI-I score of 1 (very much improved) or 2
(much improved).

Estimates of odds ratios, 95% CI, and *p*-values were based on a
logistic regression model of the response rate, with terms for treatment
group, age group, and country.

CGI-I, Clinical Global Impressions--Improvement; CGI-S, Clinical Global
Impressions--Severity; CI, confidence interval; CMH,
Cochran--Mantel--Haenszel; SE, standard error.:::: 

## Safety 

### Adverse events A total of 220/339 (64.9%) patients experienced AEs during the on-therapy period (desvenlafaxine, 69/115 [60.0%]; fluoxetine, 72/112 [64.3%]; and placebo, 79/112 [70.5%]). Most AEs were mild or moderate in severity. AEs considered by the investigator to be related to study medication were reported by 31.9% of patients (desvenlafaxine, 28.7%; fluoxetine, 32.1%; and placebo, 34.8%). Severe AEs (those that interfered significantly with patients' usual function) considered by the investigator to be unrelated to study medication were reported by 3.5% of patients (desvenlafaxine, 1.7%; fluoxetine, 5.4%; and placebo, 3.6%). In three patients, severe AEs were considered related to study medication: One desvenlafaxine-treated patient reported severe pruritus and severe macular rash and discontinued treatment. One placebo-treated patient reported severe agitation and severe anger, and a second reported severe insomnia; neither was discontinued due to those AEs. Five adolescents (0 children) discontinued due to AEs, two each from the desvenlafaxine (disinhibition; macular rash and pruritus) and placebo (vomiting; headache) groups and one from the fluoxetine group (suicidal ideation). 

### Treatment-emergent adverse events Treatment-emergent adverse events (TEAEs) reported by more than 10% of patients in any group were headache, upper abdominal pain, and nausea. [Table 3](#) shows the most frequent (≥5% in any group) TEAEs by age group, and overall. There were no statistically significant differences between desvenlafaxine or fluoxetine and placebo in the incidence of any prespecified TEAEs of clinical interest for desvenlafaxine (tier-1 TEAEs) ([Supplementary Table S2](#)). ::::table-wrap
::: caption
\[Number (%) of Patients Reporting Treatment-Emergent Adverse Events with
Incidence ≥5% in Any Group, On-Therapy Period, Safety
Population\]{.smallcaps}
:::

*Children* *Adolescents* *Overall*

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*Placebo (*n* = 42)* *Fluoxetine (*n* = 45)* *Desvenlafaxine (*n* = 43)* *Placebo (*n* = 70)* *Fluoxetine (*n* = 67)* *Desvenlafaxine (*n* = 72)* *Placebo (*n* = 112)* *Desvenlafaxine (*n* = 112)* *Desvenlafaxine (*n* = 115)*
Any TEAE 27 (64.3) 29 (64.4) 22 (51.2) 52 (74.3) 43 (64.2) 47 (65.3) 79 (70.5) 72 (64.3) 69 (60.0)
Headache 8 (19.0) 3 (6.7) 5 (11.6) 13 (18.6) 13 (19.4) 14 (19.4) 21 (18.8) 16 (14.3) 19 (16.5)
Abdominal pain upper 2 (4.8) 1 (2.2) 6 (14.0) 5 (7.1) 8 (11.9) 9 (12.5) 7 (6.3) 9 (8.0) 15 (13.0)
Nausea 3 (7.1) 4 (8.9) 2 (4.7) 7 (10.0) 9 (13.4) 6 (8.3) 10 (8.9) 13 (11.6) 8 (7.0)
Dizziness 3 (7.1) 1 (2.2) 2 (4.7) 3 (4.3) 2 (3.0) 5 (6.9) 6 (5.4) 3 (2.7) 7 (6.1)
Influenza 0 2 (4.4) 2 (4.7) 0 0 4 (5.6) 0 2 (1.8) 6 (5.2)
Nasopharyngitis 4 (9.5) 2 (4.4) 1 (2.3) 4 (5.7) 5 (7.5) 5 (6.9) 8 (7.1) 7 (6.3) 6 (5.2)
Upper respiratory tract infection 2 (4.8) 3 (6.7) 1 (2.3) 4 (5.7) 1 (1.5) 5 (6.9) 6 (5.4) 4 (3.6) 6 (5.2)
Vomiting 1 (2.4) 5 (11.1) 1 (2.3) 3 (4.3) 2 (3.0) 4 (5.6) 4 (3.6) 7 (6.3) 5 (4.3)
Diarrhea 1 (2.4) 0 4 (9.3) 2 (2.9) 3 (4.5) 1 (1.4) 3 (2.7) 3 (2.7) 5 (4.3)
Insomnia 1 (2.4) 1 (2.2) 0 2 (2.9) 4 (6.0) 4 (5.6) 3 (2.7) 5 (4.5) 4 (3.5)
Fatigue 1 (2.4) 3 (6.7) 0 1 (1.4) 3 (4.5) 2 (2.8) 2 (1.8) 6 (5.4) 2 (1.7)
Pharyngitis 2 (4.8) 3 (6.7) 1 (2.3) 0 1 (1.5) 1 (1.4) 2 (1.8) 4 (3.6) 2 (1.7)
Rash 0 3 (6.7) 0 0 1 (1.5) 1 (1.4) 0 4 (3.6) 1 (0.9)
Arthralgia 3 (7.1) 1 (2.2) 1 (2.3) 1 (1.4) 2 (3.0) 0 4 (3.6) 3 (2.7) 1 (0.9)
Fall 2 (4.8) 4 (8.9) 0 0 1 (1.5) 0 2 (1.8) 5 (4.5) 0
Constipation 3 (7.1) 0 0 1 (1.4) 0 0 4 (3.6) 0 0

TEAE, treatment-emergent adverse event.:::: 

### Deaths and serious AEs There were no deaths during the study. Five randomized patients experienced serious AEs: two assigned to fluoxetine (suicidal ideation [acute suicidality; discontinued] and suicide attempt [occurred poststudy], one patient each), three assigned to desvenlafaxine (suicidal ideation [discontinued due to lack of confidence in caregiver reliability to report patient status], disinhibition [discontinued], and postpartum hemorrhage with anemia and endometritis [occurred poststudy], one patient each), and no placebo-treated patients. The desvenlafaxine-treated patient with postpartum hemorrhage had been withdrawn from the study following a positive pregnancy test at the final treatment phase visit and delivered a healthy full-term infant. 

### Suicidality A summary of C-SSRS results for treatment-emergent suicidal ideation or behavior is presented for the safety population in [Table 4](#) (full C-SSRS results are presented in [Supplementary Table S3](#)). Treatment-emergent suicidal ideation or suicidal behavior, which included both new-onset and worsening suicidal ideation or behavior, was reported for 29 (8.6%) of 337 patients who had a C-SSRS assessment at baseline and at 1 or more postbaseline time points. A total of 29/337 (8.6%) patients had treatment-emergent suicidal ideation, and 1 patient (0.3%) also had treatment-emergent suicidal behavior. The suicidal behavior event was categorized as a preparatory act toward imminent suicidal behavior (preparatory acts or behavior; interrupted attempt) and was reported in a fluoxetine-treated adolescent ([Supplementary Table S3](#)). The patient was discontinued due to a serious AE of acute suicidality (described in "Deaths and Serious AEs" section). ::::table-wrap
::: caption
\[Summary of Treatment-Emergent Suicidal Ideation and Behavior Reported
on the Columbia-Suicide Severity Rating Scale at Any Postbaseline
Assessment, Safety Population\]{.smallcaps}
:::

*Placebo (*N* = 112)* *Fluoxetine (*N* = 110)* *Desvenlafaxine (*N* = 115)* *Total (*N* = 337)*

______________________________________________________________________

Treatment-emergent SIB^[a](#)^ 8/112 (7.1) 12/110 (10.9) 9/115 (7.8) 29/337 (8.6)
New-onset SIB^[b](#)^ 7/104 (6.7) 10/97 (10.3) 8/102 (7.8) 25/303 (8.3)
Worsening SIB^[c](#)^ 1/8 (12.5) 2/13 (15.4) 1/13 (7.7) 4/34 (11.8)
Treatment-emergent SI^[d](#)^ 8/112 (7.1) 12/110 (10.9) 9/115 (7.8) 29/337 (8.6)
New-onset SI^[e](#)^ 7/104 (6.7) 10/97 (10.3) 8/102 (7.8) 25/303 (8.3)
Wish to be dead 5 4 3 12
Nonspecific active suicidal thoughts 1 1 1 3
Active SI with any methods (no plan) without intent to act 1 5 4 10
Worsening SI^[f](#)^ 1/8 (12.5) 2/13 (15.4) 1/13 (7.7) 4/34 (11.8)
Shift to nonspecific active suicidal thoughts 1 0 0 1
Shift to active SI with any methods (no plan) without intent to act 0 1 1 2
Shift to active SI with specific plan and intent 0 1 0 1
Treatment-emergent SB^[g](#)^ 0/112 (0.0) 1/110 (0.9) 0/115 (0.0) 1/337 (0.3)
New-onset SB^[h](#)^ 0/112 (0.0) 1/110 (0.9) 0/115 (0.0) 1/337 (0.3)
Interrupted attempt 0 1 0 1
Worsening SB^[i](#)^ 0 0 0 0

There was one poststudy suicide attempt reported as a serious adverse
event that was not captured on the C-SSRS; C-SSRS was not performed
following that event. *N* represents the number of patients in this
analysis, that is, patients who had a baseline and a postbaseline C-SSRS
assessment.

Treatment-emergent SIB is defined as (1) new-onset SI or SB, (2)
worsening SI or SB, or (3) postbaseline SB on patients reporting SI at
baseline.

New-onset SIB is defined as any SI or SB reported postbaseline on
patients who reported no SI and no SB at baseline.

Worsening SIB is defined as (1) shift from SI at baseline to a more
severe SI postbaseline, (2) shift from SI at baseline (and no SB at
baseline) to any SB postbaseline, or (3) shift from SB at baseline to a
more severe SB postbaseline.

Treatment-emergent SI is defined as new-onset SI or worsening SI.

New-onset SI is defined as any SI reported postbaseline on patients who
reported no SI at baseline.

Worsening SI is defined as shift to a more severe SI postbaseline on
patients reporting SI at baseline.

Treatment-emergent SB is defined as new-onset SB or worsening SB.

New-onset SB is defined as any SB reported postbaseline on patients who
reported no SB at baseline.

Worsening SB is defined as shift to a more severe SB postbaseline on
patients reporting SB at baseline.

C-SSRS, Columbia-Suicide Severity Rating Scale; SB, suicidal behavior;
SI, suicidal ideation; SIB, suicidal ideation or behavior.:::: New-onset self-injurious behavior without suicidal intent was reported in two (1.8%) fluoxetine-treated adolescents and one (0.9%) desvenlafaxine-treated adolescent. The suicide attempt reported as a serious AE in the "Deaths and Serious AEs" section was not captured on the C-SSRS because it occurred poststudy. 

### Other safety measures The frequencies of patients with on-therapy potentially clinically important (PCI) vital sign values can be found in [Supplementary Table S4](#). Upon review of patient data by the medical monitor, eight patients (all adolescents) were deemed to have clinically important vital sign results: postural hypotension in three desvenlafaxine-treated patients (35-, 35-, and 50-mg/d doses) and in four fluoxetine-treated patients, and increased supine systolic blood pressure in one desvenlafaxine-treated patient (122--126 mm Hg at weeks 3--6; baseline, 117 mm Hg). No patients assigned to placebo had clinically important vital sign findings, and the observed changes from baseline in body mass index (BMI) were negligible. Mean changes from baseline in BMI, blood pressure, and pulse measurements are reported by age group in [Supplementary Table S5](#). Expected shifts associated with development assessed by Tanner staging were observed during the study. Clinically important ECG findings were reported for one patient assigned to fluoxetine who had Wolff--Parkinson--White syndrome at study entry, with no change over the course of the study. The frequencies of on-therapy PCI laboratory findings are presented in [Supplementary Table S6](#). Findings in nine patients (four desvenlafaxine, five fluoxetine) were determined to be clinically important: three had elevated triglycerides (two desvenlafaxine, one fluoxetine), one high prolactin (desvenlafaxine), one low hematocrit and low hemoglobin (desvenlafaxine), three positive urine protein (fluoxetine), and one abnormal liver function test (fluoxetine). No clinically important laboratory values were observed in the placebo group. Mean changes from baseline for selected laboratory values are reported by age group and treatment in [Supplementary Table S7](#).


Extracted trial result:
Outcome: CGI-I response rate (binary)
Intervention: desvenlafaxine
Comparator: placebo
Intervention events: 68
Intervention group size: 99
Comparator events: 62
Comparator group size: 99