Date: 2011-04-28
Type of information: Results
phase:
Announcement: results
Company: Shire (UK-USA)
Product: Vyvanse® (lisdexamfetamine dimesylate)
Action
mechanism: CNS stimulant. Lisdexamfetamine dimesylate is a chemically formulated long-acting, prodrug of dextroamphetamine, that belongs to the group of central nervous system stimulants. Amphetamines target the trace amine-associated receptor 1 (TAAR1). Amphetamine is also believed to exert its effects by binding to the monoamine transporters (the dopamine transporter or DAT) and increasing extracellular levels of the biogenic amines dopamine, norepinephrine (noradrenaline) and serotonin.
Disease: negative symptom predominant schizophrenia
Therapeutic area: Mental diseases - CNS diseases
Country:
Trial
details: In this study, 92 adult subjects (mean age = 42.3) first entered a prospective stability assessment period for 3 weeks, wherein symptoms and environmental settings were judged to be appropriately stable; no Vyvanse® was prescribed during this period. Subsequently in the 7-week open-label dose optimization period, subjects with clinically stable schizophrenia and predominant negative symptoms had Vyvanse® added to their established atypical antipsychotic regimen, titrating Vyvanse® to an individually-defined dose (range 20 to 70 mg per day). Subjects remained on this Vyvanse® dose during the following 3-week dose maintenance period. Subjects with reductions in negative symptoms (measured by the modified SANS-18 total score) were eligible for subsequent randomization into a double-blind withdrawal phase (4-weeks), either continuing augmentation with Vyvanse® or being switched to placebo, to assess symptom re-emergence or withdrawal symptoms. All commonly prescribed atypical antipsychotics were permitted as primary therapy. Subjects with clinically notable depressive or extrapyramidal symptoms/movement disorders (both of which may mimic negative symptoms) were excluded.
The primary efficacy measure was the modified SANS-18 score, which is the sum of all non-global SANS item ratings of affective flattening, inappropriate affect, alogia, avolition-apathy, and anhedonia-asociality. Safety measures included assessments of movement disorders, suicidal thinking, sleep quality, and amphetamine withdrawal and positive symptoms were examined.
Latest
news: Shire plc has announced positive results from a signal-finding study of Vyvanse® (lisdexamfetamine dimesylate) Capsules (CII) assessing its effect in a prospective examination of adults with negative symptom predominant schizophrenia. This study met its pre-defined primary end points. Vyvanse® is a prescription medicine currently approved in the US, Canada, and Brazil for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). Vyvanse should only be used to treat ADHD.
This investigational, phase 2, 14-week, flexible dose, multi-center study consisted of a 10 week open-label (n = 92) and a 4 week double-blind component (n = 69). Vyvanse® was administered orally as adjunctive therapy (20 to 70 mg per day, titrated over 7 weeks) to 92 clinically stable patients with predominant negative symptom schizophrenia (ages of 18 to 55), taking established maintenance doses of atypical antipsychotic medications. In the open-label, primary efficacy analysis, Vyvanse® demonstrated significant improvement (p<0.0001) in negative symptoms after 10 weeks, compared to baseline, as measured by blinded-raters using the Scale for the Assessment of Negative Symptoms modified total score or SANS-18* [LOCF; mean change of -12.9 ± 10.0 (95% CI -15.0 to -10.8)].
In order to assess the potential impact on positive symptom exacerbation, the Positive and Negative Syndrome Scale (PANSS) was administered as a secondary end point. This assessment documented the lack of positive symptom exacerbation, as Vyvanse demonstrated significant improvement from baseline to 10-week end point on both positive and overall psychiatric symptoms as measured by the PANSS positive subscale (LOCF; mean change -1.0 ± 2.2; 95% CI -1.4 to -0.5; p<0.0001) and PANSS Total score (LOCF; mean change -9.8 ± 9.0; 95% CI -11.7 to -8.0; p<0.0001). The PANSS is a commonly used measurement scale for the assessment of schizophrenia symptoms worldwide.
In the 10-week open-label phase, 23 subjects (out of 92) discontinued from the study. Five subjects discontinued due to an adverse event. Of these 5 subjects, 3 subjects discontinued due to serious adverse events. Two of the serious adverse event reports were of exacerbation of schizophrenia. The other 3 subjects discontinued due to involuntary jaw movements, elevated blood pressure or sleepiness.
Forced discontinuation criteria were also used to further ensure patient safety. These criteria included changes in positive symptoms, compliance, urine drug screen, caregiver relationship, and thoughts of self-harm or harm to others. By these criteria, 5 additional subjects were discontinued in the open-label phase (2 subjects with positive symptom change, 1 subject with non-compliance, 1 subject with self-harm thoughts, and 1 subject who terminated their caregiver relationship). The remaining subjects (n = 13) withdrew for various other reasons including: protocol violation, withdrawal by subject, or failure to meet randomization requirement.
In the double-blind phase, 13 subjects (out of 69) discontinued from the study. Two subjects withdrew due to a serious adverse event, reported as the exacerbation of schizophrenia (1 subject taking placebo and 1 subject taking Vyvanse). A third subject (taking placebo) experienced a serious adverse event of dyspepsia and was discontinued due to failure to take investigational product. Additionally, 2 subjects were discontinued because they met forced discontinuation criteria due to positive urine drug screens (1 taking placebo, 1 taking Vyvanse®).
The adverse events reported in this study included headache (14.1%), insomnia and decreased appetite (10.9% each), dizziness (8.7%), dry mouth (6.5%) and diarrhea (5.4%). Mean changes in blood pressure and pulse were all consistent with the current product labeling in ADHD. There were no notable effects on ECG or clinical laboratory assessments.
