Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD: A Phase IV, 2-Year, Open-Label Study in Europe

David R. Coghill (Lead / Corresponding author), Tobias Banaschewski, Peter Nagy, Isabel Hernández Otero, César Soutullo, Brian Yan, Beatriz Caballero, Alessandro Zuddas

    Research output: Contribution to journalArticle

    5 Citations (Scopus)
    13 Downloads (Pure)

    Abstract

    Background: Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management.

    Objectives: Our objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.

    Methods: Participants (aged 6-17 years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70 mg/day for 104 weeks. Safety monitoring included treatment-emergent adverse events (TEAEs), vital signs, electrocardiography, and growth. The TEAEs decreased appetite, weight decrease, insomnia events (including insomnia, initial insomnia, middle insomnia, and terminal insomnia), headache, and psychiatric TEAEs were pre-defined as being of special interest. Efficacy was assessed as a secondary objective using the ADHD Rating Scale IV (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale, and the CGI-Severity (CGI-S) scale.

    Results: Of 314 participants enrolled, 191 completed the study. TEAEs were reported in 89.8% of participants, led to discontinuation in 12.4%, and were reported as serious in 8.9%. TEAEs that were reported by ≥5% of participants and considered by investigators as related to LDX were decreased appetite (49.4%), weight decrease (18.2%), insomnia (13.1%), initial insomnia (8.9%), irritability (8.6%), nausea (6.7%), headache (5.7%), and tic (5.1%). The median time to first onset and duration, respectively, of TEAEs of special interest were as follows: decreased appetite, 13.5 and 169.0 days; weight decrease, 29.0 and 225.0 days; insomnia, 17.0 and 42.8 days; and headache, 22.0 and 2.0 days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4-12 weeks. Psychiatric TEAEs were infrequent: psychosis and mania (n = 1), suicidal events (suicidal ideation, n = 2; suicide attempt, n = 1), and aggression events (aggression, n = 14; anger, n = 2; hostility, n = 1). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0 bpm (95% confidence interval [CI] 5.7-8.2); systolic blood pressure (SBP), 3.4 mmHg (95% CI 2.2-4.5); and diastolic blood pressure (DBP), 3.2 mmHg (95% CI 2.2-4.2). Pre-defined thresholds for a potentially clinically important (PCI) high pulse rate were met at one or more visits by 22 participants (7.0%), for PCI high SBP were met by 45 children (22.4%) and 17 adolescents (15.2%), and for PCI high DBP were met by 78 children (38.8%) and 24 adolescents (21.4%). The mean QT interval corrected using Fridericia's formula (QTcF) decreased from baseline to LOTA (-0.6 ms [95% CI -2.3 to 1.2]; range -50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1 kg (95% CI 1.5-2.8); height, 6.1 cm (95% CI 5.6-6.7); and body mass index (BMI), -0.5 kg/m(2) (95% CI -0.7 to -0.3). There was a general shift to lower z score categories for height, weight, and BMI from baseline to LOTA. The mean change in ADHD-RS-IV from baseline to LOTA was -25.8 (95% CI -27.0 to -24.5) for total score, -12.6 (95% CI -13.4 to -11.9) for the hyperactivity/impulsivity subscale score, and -13.1 (95% CI -13.8 to -12.4) for the inattention subscale score. At LOTA, 77.9% of participants had a CGI-I score of 1 or 2. In addition, 77.3 and 69.2% of participants were classified as treatment responders, based on a CGI-I score of 1 or 2 and a ≥30% or ≥50% reduction from baseline in ADHD-RS-IV total score, respectively.

    Conclusions: The safety profile of LDX in this longer-term study was similar to that reported in previous studies. The efficacy of LDX was maintained throughout the 2-year study period.

    ClinicalTrials.gov Identifier: NCT01328756.

    Original languageEnglish
    Pages (from-to)625-638
    Number of pages14
    JournalCNS Drugs
    Volume31
    Issue number7
    Early online date30 Jun 2017
    DOIs
    Publication statusPublished - Jul 2017

    Fingerprint

    Attention Deficit Disorder with Hyperactivity
    Sleep Initiation and Maintenance Disorders
    Safety
    Confidence Intervals
    Appetite
    Blood Pressure
    Weights and Measures
    Therapeutics
    Headache
    Vital Signs
    Lisdexamfetamine Dimesylate
    Aggression
    Psychiatry
    Body Mass Index
    Heart Rate
    Hypertension
    Tics
    Suicidal Ideation
    Hostility
    Impulsive Behavior

    Cite this

    Coghill, David R. ; Banaschewski, Tobias ; Nagy, Peter ; Otero, Isabel Hernández ; Soutullo, César ; Yan, Brian ; Caballero, Beatriz ; Zuddas, Alessandro. / Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD : A Phase IV, 2-Year, Open-Label Study in Europe. In: CNS Drugs. 2017 ; Vol. 31, No. 7. pp. 625-638.
    @article{743a9518d8de4e01a37200b10e317252,
    title = "Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD: A Phase IV, 2-Year, Open-Label Study in Europe",
    abstract = "Background: Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management.Objectives: Our objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.Methods: Participants (aged 6-17 years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70 mg/day for 104 weeks. Safety monitoring included treatment-emergent adverse events (TEAEs), vital signs, electrocardiography, and growth. The TEAEs decreased appetite, weight decrease, insomnia events (including insomnia, initial insomnia, middle insomnia, and terminal insomnia), headache, and psychiatric TEAEs were pre-defined as being of special interest. Efficacy was assessed as a secondary objective using the ADHD Rating Scale IV (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale, and the CGI-Severity (CGI-S) scale.Results: Of 314 participants enrolled, 191 completed the study. TEAEs were reported in 89.8{\%} of participants, led to discontinuation in 12.4{\%}, and were reported as serious in 8.9{\%}. TEAEs that were reported by ≥5{\%} of participants and considered by investigators as related to LDX were decreased appetite (49.4{\%}), weight decrease (18.2{\%}), insomnia (13.1{\%}), initial insomnia (8.9{\%}), irritability (8.6{\%}), nausea (6.7{\%}), headache (5.7{\%}), and tic (5.1{\%}). The median time to first onset and duration, respectively, of TEAEs of special interest were as follows: decreased appetite, 13.5 and 169.0 days; weight decrease, 29.0 and 225.0 days; insomnia, 17.0 and 42.8 days; and headache, 22.0 and 2.0 days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4-12 weeks. Psychiatric TEAEs were infrequent: psychosis and mania (n = 1), suicidal events (suicidal ideation, n = 2; suicide attempt, n = 1), and aggression events (aggression, n = 14; anger, n = 2; hostility, n = 1). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0 bpm (95{\%} confidence interval [CI] 5.7-8.2); systolic blood pressure (SBP), 3.4 mmHg (95{\%} CI 2.2-4.5); and diastolic blood pressure (DBP), 3.2 mmHg (95{\%} CI 2.2-4.2). Pre-defined thresholds for a potentially clinically important (PCI) high pulse rate were met at one or more visits by 22 participants (7.0{\%}), for PCI high SBP were met by 45 children (22.4{\%}) and 17 adolescents (15.2{\%}), and for PCI high DBP were met by 78 children (38.8{\%}) and 24 adolescents (21.4{\%}). The mean QT interval corrected using Fridericia's formula (QTcF) decreased from baseline to LOTA (-0.6 ms [95{\%} CI -2.3 to 1.2]; range -50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1 kg (95{\%} CI 1.5-2.8); height, 6.1 cm (95{\%} CI 5.6-6.7); and body mass index (BMI), -0.5 kg/m(2) (95{\%} CI -0.7 to -0.3). There was a general shift to lower z score categories for height, weight, and BMI from baseline to LOTA. The mean change in ADHD-RS-IV from baseline to LOTA was -25.8 (95{\%} CI -27.0 to -24.5) for total score, -12.6 (95{\%} CI -13.4 to -11.9) for the hyperactivity/impulsivity subscale score, and -13.1 (95{\%} CI -13.8 to -12.4) for the inattention subscale score. At LOTA, 77.9{\%} of participants had a CGI-I score of 1 or 2. In addition, 77.3 and 69.2{\%} of participants were classified as treatment responders, based on a CGI-I score of 1 or 2 and a ≥30{\%} or ≥50{\%} reduction from baseline in ADHD-RS-IV total score, respectively.Conclusions: The safety profile of LDX in this longer-term study was similar to that reported in previous studies. The efficacy of LDX was maintained throughout the 2-year study period.ClinicalTrials.gov Identifier: NCT01328756.",
    author = "Coghill, {David R.} and Tobias Banaschewski and Peter Nagy and Otero, {Isabel Hern{\'a}ndez} and C{\'e}sar Soutullo and Brian Yan and Beatriz Caballero and Alessandro Zuddas",
    note = "The study was funded by Shire Development LLC. Writingand editing assistance for this paper was funded by Shire International GmbH. Shire International GmbH also funded open access",
    year = "2017",
    month = "7",
    doi = "10.1007/s40263-017-0443-y",
    language = "English",
    volume = "31",
    pages = "625--638",
    journal = "CNS Drugs",
    issn = "1172-7047",
    publisher = "Springer Verlag",
    number = "7",

    }

    Coghill, DR, Banaschewski, T, Nagy, P, Otero, IH, Soutullo, C, Yan, B, Caballero, B & Zuddas, A 2017, 'Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD: A Phase IV, 2-Year, Open-Label Study in Europe', CNS Drugs, vol. 31, no. 7, pp. 625-638. https://doi.org/10.1007/s40263-017-0443-y

    Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD : A Phase IV, 2-Year, Open-Label Study in Europe. / Coghill, David R. (Lead / Corresponding author); Banaschewski, Tobias; Nagy, Peter; Otero, Isabel Hernández; Soutullo, César; Yan, Brian; Caballero, Beatriz; Zuddas, Alessandro.

    In: CNS Drugs, Vol. 31, No. 7, 07.2017, p. 625-638.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Long-Term Safety and Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with ADHD

    T2 - A Phase IV, 2-Year, Open-Label Study in Europe

    AU - Coghill, David R.

    AU - Banaschewski, Tobias

    AU - Nagy, Peter

    AU - Otero, Isabel Hernández

    AU - Soutullo, César

    AU - Yan, Brian

    AU - Caballero, Beatriz

    AU - Zuddas, Alessandro

    N1 - The study was funded by Shire Development LLC. Writingand editing assistance for this paper was funded by Shire International GmbH. Shire International GmbH also funded open access

    PY - 2017/7

    Y1 - 2017/7

    N2 - Background: Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management.Objectives: Our objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.Methods: Participants (aged 6-17 years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70 mg/day for 104 weeks. Safety monitoring included treatment-emergent adverse events (TEAEs), vital signs, electrocardiography, and growth. The TEAEs decreased appetite, weight decrease, insomnia events (including insomnia, initial insomnia, middle insomnia, and terminal insomnia), headache, and psychiatric TEAEs were pre-defined as being of special interest. Efficacy was assessed as a secondary objective using the ADHD Rating Scale IV (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale, and the CGI-Severity (CGI-S) scale.Results: Of 314 participants enrolled, 191 completed the study. TEAEs were reported in 89.8% of participants, led to discontinuation in 12.4%, and were reported as serious in 8.9%. TEAEs that were reported by ≥5% of participants and considered by investigators as related to LDX were decreased appetite (49.4%), weight decrease (18.2%), insomnia (13.1%), initial insomnia (8.9%), irritability (8.6%), nausea (6.7%), headache (5.7%), and tic (5.1%). The median time to first onset and duration, respectively, of TEAEs of special interest were as follows: decreased appetite, 13.5 and 169.0 days; weight decrease, 29.0 and 225.0 days; insomnia, 17.0 and 42.8 days; and headache, 22.0 and 2.0 days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4-12 weeks. Psychiatric TEAEs were infrequent: psychosis and mania (n = 1), suicidal events (suicidal ideation, n = 2; suicide attempt, n = 1), and aggression events (aggression, n = 14; anger, n = 2; hostility, n = 1). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0 bpm (95% confidence interval [CI] 5.7-8.2); systolic blood pressure (SBP), 3.4 mmHg (95% CI 2.2-4.5); and diastolic blood pressure (DBP), 3.2 mmHg (95% CI 2.2-4.2). Pre-defined thresholds for a potentially clinically important (PCI) high pulse rate were met at one or more visits by 22 participants (7.0%), for PCI high SBP were met by 45 children (22.4%) and 17 adolescents (15.2%), and for PCI high DBP were met by 78 children (38.8%) and 24 adolescents (21.4%). The mean QT interval corrected using Fridericia's formula (QTcF) decreased from baseline to LOTA (-0.6 ms [95% CI -2.3 to 1.2]; range -50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1 kg (95% CI 1.5-2.8); height, 6.1 cm (95% CI 5.6-6.7); and body mass index (BMI), -0.5 kg/m(2) (95% CI -0.7 to -0.3). There was a general shift to lower z score categories for height, weight, and BMI from baseline to LOTA. The mean change in ADHD-RS-IV from baseline to LOTA was -25.8 (95% CI -27.0 to -24.5) for total score, -12.6 (95% CI -13.4 to -11.9) for the hyperactivity/impulsivity subscale score, and -13.1 (95% CI -13.8 to -12.4) for the inattention subscale score. At LOTA, 77.9% of participants had a CGI-I score of 1 or 2. In addition, 77.3 and 69.2% of participants were classified as treatment responders, based on a CGI-I score of 1 or 2 and a ≥30% or ≥50% reduction from baseline in ADHD-RS-IV total score, respectively.Conclusions: The safety profile of LDX in this longer-term study was similar to that reported in previous studies. The efficacy of LDX was maintained throughout the 2-year study period.ClinicalTrials.gov Identifier: NCT01328756.

    AB - Background: Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a persistent disorder requiring long-term management.Objectives: Our objective was to evaluate the 2-year safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with ADHD.Methods: Participants (aged 6-17 years) with ADHD received open-label, dose-optimized LDX 30, 50, or 70 mg/day for 104 weeks. Safety monitoring included treatment-emergent adverse events (TEAEs), vital signs, electrocardiography, and growth. The TEAEs decreased appetite, weight decrease, insomnia events (including insomnia, initial insomnia, middle insomnia, and terminal insomnia), headache, and psychiatric TEAEs were pre-defined as being of special interest. Efficacy was assessed as a secondary objective using the ADHD Rating Scale IV (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale, and the CGI-Severity (CGI-S) scale.Results: Of 314 participants enrolled, 191 completed the study. TEAEs were reported in 89.8% of participants, led to discontinuation in 12.4%, and were reported as serious in 8.9%. TEAEs that were reported by ≥5% of participants and considered by investigators as related to LDX were decreased appetite (49.4%), weight decrease (18.2%), insomnia (13.1%), initial insomnia (8.9%), irritability (8.6%), nausea (6.7%), headache (5.7%), and tic (5.1%). The median time to first onset and duration, respectively, of TEAEs of special interest were as follows: decreased appetite, 13.5 and 169.0 days; weight decrease, 29.0 and 225.0 days; insomnia, 17.0 and 42.8 days; and headache, 22.0 and 2.0 days. Reports of decreased appetite, weight decrease, insomnia, and headache were highest in the first 4-12 weeks. Psychiatric TEAEs were infrequent: psychosis and mania (n = 1), suicidal events (suicidal ideation, n = 2; suicide attempt, n = 1), and aggression events (aggression, n = 14; anger, n = 2; hostility, n = 1). At the last on-treatment assessment (LOTA), mean increases from baseline in vital signs were as follows: pulse rate, 7.0 bpm (95% confidence interval [CI] 5.7-8.2); systolic blood pressure (SBP), 3.4 mmHg (95% CI 2.2-4.5); and diastolic blood pressure (DBP), 3.2 mmHg (95% CI 2.2-4.2). Pre-defined thresholds for a potentially clinically important (PCI) high pulse rate were met at one or more visits by 22 participants (7.0%), for PCI high SBP were met by 45 children (22.4%) and 17 adolescents (15.2%), and for PCI high DBP were met by 78 children (38.8%) and 24 adolescents (21.4%). The mean QT interval corrected using Fridericia's formula (QTcF) decreased from baseline to LOTA (-0.6 ms [95% CI -2.3 to 1.2]; range -50 to +53). Mean changes in growth from baseline to LOTA were weight, 2.1 kg (95% CI 1.5-2.8); height, 6.1 cm (95% CI 5.6-6.7); and body mass index (BMI), -0.5 kg/m(2) (95% CI -0.7 to -0.3). There was a general shift to lower z score categories for height, weight, and BMI from baseline to LOTA. The mean change in ADHD-RS-IV from baseline to LOTA was -25.8 (95% CI -27.0 to -24.5) for total score, -12.6 (95% CI -13.4 to -11.9) for the hyperactivity/impulsivity subscale score, and -13.1 (95% CI -13.8 to -12.4) for the inattention subscale score. At LOTA, 77.9% of participants had a CGI-I score of 1 or 2. In addition, 77.3 and 69.2% of participants were classified as treatment responders, based on a CGI-I score of 1 or 2 and a ≥30% or ≥50% reduction from baseline in ADHD-RS-IV total score, respectively.Conclusions: The safety profile of LDX in this longer-term study was similar to that reported in previous studies. The efficacy of LDX was maintained throughout the 2-year study period.ClinicalTrials.gov Identifier: NCT01328756.

    U2 - 10.1007/s40263-017-0443-y

    DO - 10.1007/s40263-017-0443-y

    M3 - Article

    C2 - 28667569

    VL - 31

    SP - 625

    EP - 638

    JO - CNS Drugs

    JF - CNS Drugs

    SN - 1172-7047

    IS - 7

    ER -