A randomized, double-blind, dose-controlled study of the use of dexmedetomidine alone for procedural sedation of children and adolescents undergoing MRI scans.

BACKGROUND: Dexmedetomidine is a selective α2-adrenergic agonist originally approved for sedation of adults in the intensive care unit and subsequently approved for procedural sedation in adults undergoing medical procedures. Dexmedetomidine is widely used off-label for procedural sedation in children. AIMS: To evaluate efficacy and safety of monotherapy dexmedetomidine for magnetic resonance imaging procedural sedation of children ≥1month-<17years across three ascending doses. METHODS: Randomized, double-blind, dose-ranging study of procedural sedation recruited patients at USA and Japanese sites from February 2020 to November 2021. Patients were stratified into Cohort A (≥1month-<2years) or Cohort B (≥2-<17years). Cohort A loading doses/maintenance infusions: 0.5 mcg/kg/0.5 mcg/kg/h, 1.0 mcg/kg/1.0 mcg/kg/h, and 1.5 mcg/kg/1.5 mcg/kg/h. Cohort B loading doses/maintenance infusions: 0.5 mcg/kg/0.5 mcg/kg/h, 1.2 mcg/kg/1.0 mcg/kg/h, and 2.0 mcg/kg/1.5 mcg/kg/h. Primary endpoint was percentage of overall patients completing MRI without rescue propofol at the high versus low dose. Key secondary endpoint was percentage in each age cohort who did not require propofol at the high versus low dose. RESULTS: One hundred twenty-two patients received high- (n = 38), middle- (n = 42), or low-dose (n = 42) dexmedetomidine. A greater percentage completed MRI without propofol rescue, while receiving high- versus low-dose dexmedetomidine (24/38 [63.2%] vs. 6/42 [14.3%]) (odds ratio: 10.29, 95% confidence interval: 3.47-30.50, p < .001). Similar results were seen in both age cohorts. The most common adverse events were bradypnea, bradycardia, hypertension, and hypotension, and the majority were of mild-to-moderate severity. CONCLUSIONS: Dexmedetomidine was well tolerated. The high dose was associated with meaningfully greater efficacy compared with lower doses. Based on these results, the recommended starting dose for procedural sedation in children ≥1month-<2years is loading dose 1.5 mcg/kg/maintenance infusion 1.5 mcg/kg/h; children ≥2-<17years is loading dose 2.0 mcg/kg/maintenance infusion 1.5 mcg/kg/h.

Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder.

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.

Pharmacokinetics and Tolerability of Single-Ascending Doses of Desvenlafaxine Administered to Children and Adolescents with Major Depressive Disorder.

OBJECTIVE: To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory. METHODS: The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents. CONCLUSIONS: Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.

Safety and tolerability of desvenlafaxine in children and adolescents with major depressive disorder.

OBJECTIVE: The purpose of this study was to assess long-term safety and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) in children and adolescents with major depressive disorder (MDD). METHODS: An 8 week, multicenter, open-label, fixed-dose study of children (ages 7-11 years) and adolescents (ages 12-17 years) with MDD was followed by a 6 month, flexible-dose extension study. Patients were administered desvenlafaxine 10-100 mg/day (children) or 25-200 mg/day (adolescents) for a total of 8 months. Treatment-emergent adverse events (AEs), withdrawals because of AEs, laboratory tests, vital signs, and the Columbia Suicide-Severity Rating Scale (C-SSRS) were collected. Eight month safety results from the lead-in plus extension studies are reported for extension study participants, using lead-in study day -1 as baseline. RESULTS: Forty patients were enrolled in both studies (20 children; 20 adolescents). Of those, four children and three adolescents withdrew because of AEs. Treatment-emergent AEs reported by three or more patients were upper abdominal pain (15%) and headache (15%) in children, and somnolence (30%), nausea (20%), upper abdominal pain (15%), and headache (15%) in adolescents. Negativism (oppositional behavior) in a child was the single serious AE reported. No deaths occurred during the lead-in or extension studies. Mean pulse rates demonstrated statistically significant increases from lead-in study baseline to final evaluation (children, +5.2 bpm; adolescents, +5.9 bpm; p≤0.05). No statistically significant change in blood pressure was observed at final evaluation. Two adolescents (0 children) reported suicidal ideation on the C-SSRS at screening assessment and during the lead-in and/or extension trials; one adolescent reported suicidal ideation after screening only. CONCLUSIONS: Long-term (8 month) treatment with desvenlafaxine was generally safe and well tolerated in depressed children and adolescents.