Date: 2011-12-08
Type of information: Initiation of preclinical development
phase: 2
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: adjunctive therapy to primary antidepressant treatment in adults with partial or full remission of recurrent major depressive disorder (MDD) and significant, persistent cognitive impairments
Therapeutic area: Mental diseases - CNS diseases
Country:
Trial
details: This exploratory, double-blind, placebo-controlled, parallel-group, multi-center study consisted of a two-week screening period, a nine-week double-blind period and a two-week single-blind period. During the entire study, subjects continued taking established maintenance doses of antidepressant monotherapy. Subjects in this study had mild or less than mild depressive symptoms (total score of less than 18 on the Montgomery-Åsberg Depression Rating Scale [MADRS] at screening and baseline). The screening was followed by 1:1 randomization to Vyvanse (n = 71) or placebo (n = 72) augmentation for 9 weeks. Double-blind Vyvanse (or placebo) was administered orally as adjunctive therapy (20 to 70 mg per day, titrated over the initial 6 weeks), with the optimal individual dose being continued during a 3-week dose maintenance period. A 2-week single-blind phase followed the double-blind phase wherein all subjects were administered placebo.
A total of 143 subjects (aged 18 to 55) entered the study with at least 8 weeks of maintenance on their antidepressant monotherapy. Permitted antidepressants included the generic or branded forms of selective serotonin reuptake inhibitors (SSRIs). The subjects had no greater than mild depressive symptoms (MADRS total score less than 18) and continued to exhibit significant executive function impairments (EFI; more than 1 standard deviation from normal; GEC T-score of more than 60 on the BRIEF-A self-report) during the screening period and at baseline. The subsequent 9-week double-blind phase consisted of a 6-week dose-optimization period titrating Vyvanse® from the initial 20-mg dose to an optimal dose of up to 70 mg of Vyvanse® or matching placebo, and followed by a 3-week dose maintenance period to evaluate clinical response. Subjects who completed the double-blind phase of the study entered a single-blind phase with placebo over a 2-week period to evaluate the maintenance of treatment response and safety of the withdrawal of amphetamine. Subjects with either a prior diagnosis of ADHD or who fulfilled DSM-IV-TR® criteria for ADHD were excluded. Subjects who had symptomatic manifestations that contraindicated treatment with Vyvanse® or may have confounded efficacy or safety assessments were also excluded. In addition, subjects treated with medications such as serotonin-norepinephrine reuptake inhibitors (SNRIs), typical or atypical antipsychotics, mood stabilizers, tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) were excluded from the study.
The primary efficacy was the mean change in GEC T-scores of the BRIEF-A (self-report) from baseline to the end of the 9-week double-blind phase. Additionally, the study included a number of secondary end points. Safety assessments included TEAEs, vital signs, 12-lead ECG, clinical laboratory assessments, and Suicidality Tracking Scale (STS).
Latest
news: Shire has announced positive Phase II results in a prospective clinical study of Vyvanse® (lisdexamfetamine dimesylate) Capsules, (CII) as adjunctive therapy to primary antidepressant treatment in adults with partial or full remission of recurrent major depressive disorder (MDD) and significant, persistent cognitive impairments.
Shire is investigating the use of Vyvanse® as adjunctive therapy for patients with MDD. Some patients with MDD may continue to have cognitive impairment despite resolution of depressive symptoms following antidepressant therapy, although the time course and prevalence of cognitive symptoms in patients with MDD has not been fully characterized. This study, which examined MDD patients with partially or fully remitted symptoms of depression, met its primary end point, which was, change from baseline to end point in the Global Executive Composite (GEC) T-score of the Behavioral Rating Inventory of Executive Function - Adult Version (BRIEF-A) self-report. The BRIEF-A (self-report) is a 75-item instrument that assesses behaviors associated with specific domains of executive functions in adults. This scale is used in a variety of conditions in addition to depression.
On the primary efficacy measure, GEC T-score of the BRIEF-A self-report, Vyvanse® was superior to placebo. "These data are intriguing in that they remind us of the impairment in executive functioning that patients may continue to manifest with mild depressive symptoms," stated Dr. Jeffrey Jonas, Senior Vice President of Research and Development for Shire's Specialty Pharmaceuticals business. "We will explore with regulatory agencies how these new findings might support our development program for Vyvanse® as an adjunctive therapy in patients with MDD."
On a secondary end point, mean change in MADRS total score from baseline to end point, Vyvanse® was superior to placebo. The MADRS is a validated scale which is commonly used by investigators to assess the severity of depressive illness. "The results of this secondary end point (MADRS) reinforce Shire's decision to investigate Vyvanse® as adjunctive therapy in MDD. This trial reflects Shire's approach to patient-centric targeting to potentially optimize outcomes in otherwise heterogeneous disorders," added Dr. Jonas.
Over all periods of the study, 24 subjects (out of 143) discontinued (11 on Vyvanse® and 13 on placebo) treatment. During the double-blind phase, 5 subjects withdrew due to an adverse event (4 on Vyvansev and 1 on placebo). The 4 events which led to discontinuation from Vyvanse® were loss of consciousness, suicidal ideation, rash, and worsening of depression. In the placebo group, 1 subject discontinued due to headaches. During the double-blind phase, 5 serious adverse events (SAEs) were reported: 2 on Vyvanse® (aforementioned loss of consciousness [related], suicidal ideation [not related]), and 3 on placebo (viral gastroenteritis, rhabdomyolysis, and salmonellosis). Treatment-emergent adverse events (TEAEs) ( more than 5% and at least two times placebo rate) occurring in the Vyvanse® treatment arm were decreased appetite (22.5%), insomnia (14.1%), urinary tract infection (9.9%), hyperhidrosis (5.6%), and somnolence (5.6%). 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.
