6 results
Effects of Viloxazine ER (Qelbree®) on Weight and Height Trajectories: Interim Results From a Long-term, Open-Label Extension Trial in Pediatric ADHD
- Azmi Nasser, Joseph Hull, Jami Earnest, Jennifer Koch, Tesfaye Liranso, Zulane Maldonado-Cruz, Jonathan Rubin, Ann Childress
-
- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 218
-
- Article
-
- You have access Access
- Export citation
-
Introduction
Stimulant medications and the norepinephrine reuptake inhibitor, atomoxetine, contain warnings regarding potential for slowing of growth (weight and height) in children and recommend monitoring of growth when using these medications for pediatric ADHD. Viloxazine ER (viloxazine extended-release capsules; Qelbree®), is a nonstimulant medication, FDA-approved for ADHD in adults and children (≥6 years of age). Viloxazine ER has pharmacologic differences from other approved ADHD medications and might not affect growth in the same manner as other therapies. A safety analysis was conducted to determine viloxazine ER effects on growth and weight trajectories in pediatric ADHD patients with long-term use.
MethodsData were evaluated from five DBPC, phase 2 and 3 clinical trials and an ongoing long-term, open-label extension (OLE) trial (NCT02736656). Viloxazine ER doses during the trials ranged from 100–400 mg/day (age 6–11 yrs) or 100–600 mg/day (age 12–17 yrs). Height and weight were evaluated pretreatment in both DB and OLE every 3 months during the OLE, and converted into percentile values and corresponding z-scores using Centers for Disease Control (CDC) normal growth curves to evaluate growth trajectories. The incidence of weight- and growth-related adverse events (AEs) terms were also evaluated.
ResultsAt the time of data cut (31 July 2019), 1097 subjects had received at least one dose of viloxazine ER in the OLE (66% male, mean (SD) age 10.8 (3.06), 59% age 6–11, mean (SD) BMI 18.8 (3.42) kg/m2, height 146.7 (17.46) cm, weight 42.1 (16.01) kg. During the OLE, mean (SE) z-scores for height and weight were between -1 and 1 for all timepoints, indicating growth measures within a normal range compared with expected values. Similar results were observed when weight and height were analyzed by sex and by age categories. Growth data were available for 338 subjects at 12 months. Among these subjects, the mean (SD) change from baseline in weight-for-age z-score was -0.2 (0.5) and height-for-age z-score was -0.14 (1.1). Adverse events relevant to weight and growth in the DB trials (incidence ≥ 1%) included (viloxazine ER [100–600 mg/day] n=1117 vs. placebo n=487): decreased appetite (8.1% vs. 0.8%), nausea (5.1% vs. 2.7%), vomiting (4.7% vs. 1.4%), weight increase (0.4% vs. 1.2%) and weight decrease (1.3% vs. 0.4%), and increased appetite (0.2% vs. 1.2%). During the OLE weight-and growth-related AEs reported for ≥ 1% of subjects were: decreased appetite 5.8%, vomiting 2.7%, nausea 2.4%, weight decreased 2.3%, and weight increased 2.0%.
ConclusionsOver time, pediatric subjects taking viloxazine ER, on average, maintained normal weight and height relative to the CDC’s child growth charts. However, because Qelbree may affect weight, it is recommended that healthcare providers check patient weight before starting and while using viloxazine ER.
FundingSupernus Pharmaceuticals, Inc.
114 An Assessment of QTc Effects With SPN-812 (Extended-Release Viloxazine) in Healthy Adults
- Azmi Nasser, Shamia L. Faison, Tesfaye Liranso, Toyin Adewole, Maurizio Fava, Robert Kleiman, Stefan Schwabe
-
- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, p. 274
-
- Article
-
- You have access Access
- Export citation
-
Study Objective:
SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) under investigation as a treatment for attention-deficit/hyperactivity disorder (ADHD). One concern for any new drug is prolongation of the QT interval, which is associated with increased risk for potentially very harmful ventricular cardiac arrhythmias such as torsades de pointes (TdP). The objective of this study was to assess the effects of SPN-812 at a supratherapeutic dose (1800 mg once daily [QD]) on cardiac repolarization (QTc) in healthy adults.
Method:This study was a Phase 1, double-blind (except for the positive control moxifloxacin), randomized, 3-period, 6-sequence crossover design in healthy adult male and female subjects evaluating the electrocardiographic effects of SPN-812. Subjects were randomized to receive a sequence of all 3 treatments – placebo, 400 mg moxifloxacin (positive control), and 1800 mg SPN-812 (supratherapeutic dose). Treatment was given for 2 consecutive days (separated by a washout of at least 4 days). The primary endpoint was based on concentration-QTc effect modeling, evaluating the relationship between plasma concentrations of SPN-812 and its metabolite 5-hydroxyviloxazine glucuronide (5-HVLX-gluc) with the placebo-adjusted change from baseline in QTcI, ΔΔQTcI (QT interval corrected for HR based on the individual-specific QT interval correction method). Secondary endpoints included time point change from baseline in QTcI, QTcF, HR, PR, and QRS; evaluation of the relationship between the plasma concentration of viloxazine and 5-HVLX-gluc and the placebo-adjusted change from baseline in HR, PR, QRS, and QTcF; evaluation of the relationship between the plasma concentration of moxifloxacin and ΔΔQTcI to demonstrate assay sensitivity; and changes in ECG morphology. Safety endpoints included assessment of adverse events and other parameters.
Results:The relationship between ΔΔQTcI and viloxazine plasma concentration demonstrated a negative slope (p=0.0012). Predicted mean ΔΔQTcI (2-sided 90% CI) for SPN-812 was -9.7 ms (-11.3, -8.1) at the mean Cmax of 12.4 μg/mL. The relationship of 5-HVLX-gluc and ΔΔQTcI similarly demonstrated a predicted negative slope (p=0.0007) with a predicted mean ΔΔQTcI (2-sided 90% CI) of -9.2 ms (-10.8, -7.8) at the mean Cmax of 10.0 μg/mL. Assay sensitivity was confirmed. Concentration-effect modeling demonstrated no relationship between plasma concentrations of viloxazine and 5-HVLX-gluc and other ECG parameters. The secondary time point analyses demonstrated no effect of SPN-812 on QTcI or other ECG intervals. SPN-812 produced no changes in ECG T wave or U wave morphology.
Conclusions:Data from this Phase 1 thorough QT study demonstrate that a supratherapeutic dose of SPN-812, 1800 mg QD, has no effect on cardiac repolarization or other ECG parameters, and is thus not associated with a risk for cardiac arrhythmias such as TdP.
Funding Acknowledgements:This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.
111 Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P301) Assessing Efficacy and Safety of Extended-Release Viloxazine in Children with ADHD
- Azmi Nasser, Joseph T. Hull, Fatima A. Chowdhry, Toyin Adewole, Tesfaye Liranso, Stefan Schwabe
-
- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, p. 272
-
- Article
-
- You have access Access
- Export citation
-
Study Objective:
SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P301) evaluated the efficacy and safety of once-daily SPN-812 at doses of 100 and 200 mg compared to placebo in children ages 6-11yrs with ADHD.
Method:Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, a Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. This investigation was conducted at 34 study sites in the United States. Subjects (N=477) were randomized 1:1:1 to placebo:100 mg SPN-812:200 mg SPN-812. The 6-week treatment period included up to 1 week of titration and 5 weeks of maintenance (intent-to-treat population: N=460; placebo=155, 100 mg=147, 200 mg=158). The primary efficacy endpoint was the change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) scores at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and in Weiss Functional Impairment Rating Scale-Parent Version (WFIRS-P) total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical exams, electrocardiograms, and the Columbia-Suicide Severity Rating Scale.
Results:Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 100 mg and 200 mg SPN-812 treatment groups beginning at week 1 (p=0.0004, p=0.0244; respectively) through EOS (p=0.0004, p<0.0001; respectively). Significant improvement at EOS for both 100 mg and 200 mg SPN-812 compared to placebo was also observed in CGI-I score (p=0.0020, p<0.0001; respectively), Connors 3-PS Composite T-score (p=0.0003, p=0.0002; respectively), and in WFIRS-P total average score (p=0.0019, p=0.0002, respectively). The most common (≥5%) treatment-related AEs reported were somnolence, decreased appetite, and headache.
Conclusions:In this study, SPN-812 at 100 mg and 200 mg doses met the primary and secondary objectives with statistical significance. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.
This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).
Funding Acknowledgements:This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.
112 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P302): Efficacy and Safety of Extended-Release Viloxazine in Adolescents with ADHD
- Azmi Nasser, Joseph T. Hull, Fatima A. Chowdhry, Toyin Adewole, Tesfaye Liranso, Stefan Schwabe
-
- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 272-273
-
- Article
-
- You have access Access
- Export citation
-
Study Objective:
SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P302) evaluated the efficacy and safety of once-daily SPN-812 at doses of 200 and 400 mg compared to placebo in adolescents ages 12-17yrs with ADHD.
Method:Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. This investigation was conducted at 34 study sites in the United States. Subjects (N=310) were randomized 1:1:1 to placebo:200 mg SPN-812:400 mg SPN-812. The treatment period included up to 1 week of titration and 5 weeks of maintenance (intent-to-treat population: N=301; placebo=104, 200 mg=94, 400 mg=103). The primary efficacy endpoint was change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) score at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and Weiss Functional Impairment Rating Scale-Parent Form (WFIRS-P) total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical exams, electrocardiograms, and the Columbia-Suicide Severity Rating Scale.
Results:Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 200 mg and 400 mg SPN-812 treatment group at EOS (p=0.0232, p=0.0091; respectively). Significant improvement in CGI-I score at EOS for both 200 mg and 400 mg SPN-812 compared to placebo was also observed (p=0.0042, p=0.0003; respectively). No significant change was observed at either dose compared to placebo in the Conners 3-PS Composite T-score (p=0.6854, p=0.0518; respectively), or the WFIRS-P total average score (p=0.2062, p=0.0519; respectively). The most common (≥5%) treatment-related AEs were somnolence, decreased appetite, fatigue, headache, and nausea.
Conclusions:In this study, SPN-812 met the primary objective for both the 200 and 400 mg doses, and a key secondary objective (CGI-I) for both the 200 and 400 mg doses. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.
This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).
Funding Acknowledgements:This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.
113 Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P303) Assessing Efficacy and Safety of Extended-Release Viloxazine in Children with ADHD
- Azmi Nasser, Joseph T. Hull, Fatima A. Chowdhry, Toyin Adewole, Tesfaye Liranso, Stefan Schwabe
-
- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 273-274
-
- Article
-
- You have access Access
- Export citation
-
Study Objective:
SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P303) evaluated the efficacy and safety of once-daily SPN-812 at doses of 200 and 400 mg compared to placebo in children ages 6-11yrs with ADHD.
Method:Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. Subjects were enrolled at 31 study sites in the United States. Subjects (N=313) were randomized 1:1:1 to placebo:200 mg SPN-812:400 mg SPN-812. Treatment included up to 3 weeks of titration and 5 weeks of maintenance (intent-to-treat population: N=301; placebo=97, 200 mg=107, 400 mg=97). The primary efficacy endpoint was change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) score at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and in Weiss Functional Impairment Rating Scale-Parent Form (WFIRS-P) total average score. Safety assessments included adverse events (AEs) among other measures.
Results:Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 200 mg and 400 mg SPN-812 treatment group at EOS (p=0.0038, p=0.0063; respectively). Significant improvement in CGI-I score at EOS for both 200 mg and 400 mg SPN-812 was also observed (p=0.0028, p=0.0099; respectively). Significant improvement was observed for the 200 mg SPN-812 dose compared to placebo in the Conners 3-PS Composite T-score (p=0.0064), but not for the 400 mg dose (p=0.0917). No significant improvement was observed in either dose group in the WFIRS-P total average score (p=0.0651, p=0.1680; respectively). The most common (≥5%) treatment-related AEs were somnolence, decreased appetite, fatigue, headache, and upper abdominal pain.
Conclusions:In this study, SPN-812 met the primary objective for both the 200 and 400 mg doses and the key secondary objective (CGI-I) for both the 200 and 400 mg doses with statistical significance. A second key secondary objective (Conners 3-PS) for the 200 mg dose was also met. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.
This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).
Funding Acknowledgements:This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.
9 Phase 3 Randomized, Double-blind, Placebo-Controlled Studies Evaluating Efficacy and Safety of Extended-Release Viloxazine for Pediatric ADHD
- Azmi Nasser, Janet K. Johnson, Toyin Adewole, Tesfaye Liranso, Ronald Marcus
-
- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 177-178
-
- Article
-
- You have access Access
- Export citation
-
Study Objectives
Although stimulants are commonly used for attention-deficit/hyperactivity disorder (ADHD), 10–30% of patients have an inadequate response, adverse events, or comorbidities preventing use. Thus, there is a need for safe, effective nonstimulant options. Extended-release viloxazine (SPN-812), a nonstimulant, is currently in development for the treatment of ADHD in children and adolescents. SPN-812 is a structurally distinct, bicyclic norepinephrine reuptake inhibitor with selective serotonergic activity. Results of the Phase 2 program demonstrated efficacy (improved mean ADHD Rating Scale-IV total score) and safety of SPN-812 in children (6–12 years), as well as an onset of action within 1–2 weeks.
MethodFour ongoing Phase 3 randomized, double-blind, placebo-controlled, outpatient, US studies are investigating the efficacy and safety of once-daily SPN-812 for ADHD in children (ages 6–11; 100–400mg) and adolescents (ages 12–17; 200–600mg). Two studies are enrolling children and two are enrolling adolescents. Eligible subjects are required to have minimum baseline scores of ≥28 for ADHD-RS-5 and ≥4 for Clinical Global Impression-Severity scale (CGI-S). These studies will randomize ∼1200 subjects, with ∼800 subjects receiving SPN-812 over a 1–3-week titration and 5-week maintenance period. The primary endpoint in all studies is mean change from baseline to end of study (EOS) in ADHD-RS-5 total score for SPN-812 vs. placebo. Secondary endpoints include change from baseline to EOS in 30% responder rate (% change: ADHD RS 5); Hyperactivity/Impulsivity and Inattention ADHD-RS-5 subscale scores; Conners 3 Rating Scale (parent and self-report); CGI-S/CGI-I (Improvement); Weiss Functional Impairment Rating Scale (parent report); Parenting Stress Index (children); and Stress Index for Parents of Adolescents (adolescents) after 6–8 weeks of treatment. Safety is assessed via adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and the Columbia-Suicide Severity Rating Scale. Phase 3 completers are offered the option of enrolling in an open-label extension study (OLE; up to 3 years) with a starting dose of 100/200mg (children/adolescents). Data will be summarized with descriptive statistics and analyzed using appropriate statistical methods.
ResultsAs of August 2018, enrollment in 1 child study is complete, and the other 3 trials are at ∼89%; rollover into the OLE is ∼90%.
ConclusionsThere is an unmet need for nonstimulant ADHD treatment for children and adolescents that is effective, long-acting, and well tolerated. SPN-812 is being investigated in four Phase 3 randomized, placebo-controlled studies for the treatment of children and adolescents with ADHD, based on demonstrated efficacy and safety in the Phase 2 program.
This study is an encore of a poster presentation at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP).
Funding Acknowledgements: Supernus Pharmaceuticals, Inc.