5 results
Dexmedetomidine Orally Dissolving Film for Acute Agitation Associated with Schizophrenia or Bipolar Disorder: SERENITY I and SERENITY II Trials
- Leslie L. Citrome, Sheldon H. Preskorn, Lavanya Rajachandran, Robert Risinger
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- Journal:
- CNS Spectrums / Volume 27 / Issue 2 / April 2022
- Published online by Cambridge University Press:
- 28 April 2022, p. 242
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Episodes of acute agitation associated with psychiatric disorders are often managed in emergency and inpatient settings. These trials evaluated the efficacy, safety, and tolerability of dexmedetomidine orally dissolving film (ODF), an investigational treatment for acute agitation associated with schizophrenia (SERENITY I) or bipolar disorder (SERENITY II). Dexmedetomidine ODF is a highly selective agonist of alpha 2 adrenergic receptors that modulate norepinephrine release from the locus coeruleus. Two randomized, double-blind, placebo-controlled Phase 3 trials in 15 U.S. sites included participants aged 18 to 75 with acute agitation and a DSM-5 diagnosis of schizophrenia or schizoaffective disorder (Serenity I) or bipolar disorder I or II (Serenity II). Agitation was defined as ³14 on the Positive and Negative Syndrome Scale-Excited Component (PEC) at screening and baseline, and ³4 on at least 1 of the 5 PEC items (poor impulse control, tension, hostility, uncooperativeness, and excitement) at baseline. Randomization was 1:1:1 to dexmedetomidine ODF 120 or 180 mcg or matching placebo. All participants self-administered study drugs. For persistent or recurrent agitation after 2 hours, investigators could redose a half-dose. The primary endpoint was changed from baseline in PEC total at 2 hours. The secondary endpoint was the earliest time at which a statistically significant separation from placebo occurred.A total of 380 patients were randomized in each trial (N = 760). All doses of dexmedetomidine ODF met the primary endpoint of change from baseline in PEC at 2 hours vs placebo (P < .001). Statistically significant improvement in PEC occurred as early as 20 minutes with the 180 mcg dose in both trials. A second (half-strength) dose was given to 10 (4.0%) participants in the 180 mcg groups, 34 (13.3%) in the 120 mcg groups, and 58 (23.0%) in the placebo groups in Serenity 1 and Serenity 2. There were no drug-related serious or severe TEAEs in either trial. No participant was unarousable by the Agitation and Calmness Evaluation Scale. For dexmedetomidine 180 mcg, 120 mcg, and placebo, the incidence of TEAEs was 37.3%, 39.5%, and 15.1% in Serenity 1 and 35.7%, 34.9%, and 17.5% in Serenity 2. Somnolence was the most common TEAE in both trials (22% Serenity I; 21% Serenity 2). Of 110 somnolence reports, 75% were mild and 25% moderate. In 2 Phase 3 trials, the investigational treatment, dexmedetomidine ODF, effectively treated acute agitation associated with schizophrenia or bipolar disorder, with onset of action as early as 20 minutes at the 180 mcg dose. Both doses of dexmedetomidine ODF produced a calming effect without unarousable sedation. Mild or moderate somnolence was the most common AE. Dexmedetomidine ODF is a selective alpha-2 adrenergic receptor agonist that allows self-administration, making it a potential addition to noninvasive treatments for acute agitation associated with schizophrenia or bipolar disorder.
FundingBioXcel Therapeutics
A Combination of Olanzapine and Samidorphan in Adults with Schizophrenia and Bipolar I Disorder: Overview of Clinical Data
- Leslie Citrome, Christine Graham, Adam Simmons, Ying Jiang, Mark S. Todtenkopf, Bernard L. Silverman, Lauren DiPetrillo, Hannah Cummings, Lei Sun, David McDonnell
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, p. 170
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Objectives
Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is hindered by significant weight gain. A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data.
MethodsThe OLZ/SAM development program consists of 18 phase 1–3 clinical studies evaluating antipsychotic and weight mitigation efficacy of OLZ/SAM, along with pharmacokinetics, safety, and tolerability. Safety evaluation also included metabolic laboratory assessments.
ResultsOLZ/SAM significantly improved psychotic symptoms (measured by Positive and Negative Syndrome Scale); improvements were similar to that observed with olanzapine vs placebo. OLZ/SAM resulted in significantly less weight gain than olanzapine. Additionally, 2 long-term phase 3 extension studies confirmed the durability of antipsychotic effect, as well as stabilization of weight and metabolic parameters in those continuing treatment. Supporting the potential use of OLZ/SAM in BD-I, OLZ/SAM or olanzapine resulted in bioequivalent olanzapine plasma concentrations, and OLZ/SAM did not affect lithium or valproate pharmacokinetics. OLZ/SAM treatment had no clinically relevant effects on ECG parameters (including QTc interval). OLZ/SAM and olanzapine safety were similar, except for reduced weight gain with OLZ/SAM; no additional safety risks were identified.
ConclusionData across 18 OLZ/SAM studies in >1600 subjects support an antipsychotic efficacy and safety profile for OLZ/SAM that is similar to olanzapine, with significantly less weight gain than olanzapine. OLZ/SAM is a potential new treatment for schizophrenia and BD-I patients needing efficacious long-term treatment with reduced risk of weight gain.
FundingAlkermes, Inc.
Effect of aripiprazole lauroxil in patients with acute schizophrenia as assessed by the Positive and Negative Syndrome Scale—supportive analyses from a Phase 3 study
- Leslie Citrome, Robert Risinger, Andrew J. Cutler, Yangchun Du, Jacqueline Zummo, Henry A. Nasrallah, Bernard L. Silverman
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- Journal:
- CNS Spectrums / Volume 23 / Issue 4 / August 2018
- Published online by Cambridge University Press:
- 19 June 2017, pp. 284-290
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Objective
Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints.
MethodsPatients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression–Improvement (CGI-I) scale score, was also analyzed.
ResultsOf 622 patients who were randomized, 596 had ≥1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92–94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (p<0.001) improved by Day 85 with both AL doses, with significantly lower scores starting from Day 8 in most instances. Treatment response rates were significantly (p<0.001) greater with both doses of AL vs placebo.
ConclusionAL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety.
Best Clinical Practice With Ziprasidone IM: Update After 2 Years of Experience
- Dan L. Zimbroff, Michael H. Allen, John Battaglia, Leslie Citrome, Avrim Fishkind, Andrew Francis, Daniel L. Herr, Douglas Hughes, Marc Martel, Horacio Preval, Ruth Ross
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- Journal:
- CNS Spectrums / Volume 10 / Issue S11 / 2005
- Published online by Cambridge University Press:
- 07 November 2014, pp. 1-15
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Acute agitation is a common psychiatric emergency often treated with intramuscular (IM) medication when rapid control is necessary or the patient refuses to take an oral agent. Conventional IM antipsychotics are associated with side effects, particularly movement disorders, that may alarm patients and render them unreceptive to taking these medications again. Ziprasidone (Geodon®) is the first second-generation, or atypical, antipsychotic to become available in an IM formulation. Ziprasidone IM was approved by the Food and Drug Administration in 2002 for the treatment of agitation in patients with schizophrenia. In October 2004, a roundtable panel of physicians with extensive experience in the management of acutely agitated patients met to review the first 2 years of experience with this agent. This monograph, a product of that meeting, discusses clinical experience to date with ziprasidone IM and offers recommendations on its use in various settings.
In clinical trials, patients treated with ziprasidone IM demonstrated significant and rapid (within 15-30 minutes) reduction in agitation and improvement in psychotic symptoms, agitation, and hostility to an extent greater than or equal to that attained with haloperidol IM. Tolerability of ziprasidone IM was superior to that of haloperidol IM, with a lower burden of movement disorders. Clinical trials have also shown that ziprasidone IM can be administered with benzodiazepines without adverse consequences. Transition from IM to oral ziprasidone has been well tolerated, with maintenance of symptom control. The most common adverse events associated with ziprasidone IM were insomnia, headache, and dizziness in fixed-dose trials and insomnia and hypertension in flexible-dose trials. No consistent pattern of escalating incidence of adverse events with escalating ziprasidone doses has been observed. Changes in QTc interval associated with ziprasidone at peak serum concentrations are modest and comparable to those seen with haloperidol IM. Results of randomized clinical trials of ziprasidone IM have been corroborated in studies in real-world treatment settings involving patients with extreme agitation or a recent history of alcohol or substance abuse. In these circumstances, clinically significant improvement was seen within 30 minutes of ziprasidone IM administration, without regard to the suspected underlying etiology of agitation. Agents with a good safety/tolerability profile, such as ziprasidone IM, may be more cost effective long term than older agents, due to reduced incidence of acute adverse effects (eg, acute dystonia) that often require extended periods of observation. Additional trials of ziprasidone IM in agitated patients in a variety of clinical settings are warranted to generate comparative risk/benefit data with conventional agents and other second-generation antipsychotics.
Contributors
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- By Leslie Citrome, Alan J. Cross, Judith Dunn, Kenneth R. Evans, Douglas E. Feltner, Philip D. Harvey, Amir Kalali, Richard S. E. Keefe, Michael Krams, Joseph Kwentus, Matthew Macaluso, Craig H. Mallinckrodt, Geert Molenberghs, Nuala Murphy, Ginette Nachman, Sheldon Preskorn, William R. Prucka, Penny Randall, Frank D. Yocca, Gwen L. Zornberg
- Edited by Amir Kalali, University of California, San Diego, Sheldon Preskorn, Joseph Kwentus, University of Mississippi, Stephen M. Stahl, University of California, San Diego
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- Book:
- Essential CNS Drug Development
- Published online:
- 05 July 2012
- Print publication:
- 07 June 2012, pp vi-viii
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