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Number Needed to Treat and Number Needed to Harm From Two Phase 3 Studies of Sublingual Dexmedetomidine for Treating Acute Agitation in Patients With Schizophrenia and Bipolar Disorder
- Citrome L, Risinger R, Rajachandran L, Patton E, Robison H
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 226
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Background
Episodes of acute agitation can occur in individuals who suffer from schizophrenia or bipolar disorder and these can be a significant challenge for patients and for those who provide care to them. Sublingual dexmedetomidine is a selective alpha2-adrenergic receptor agonist that was recently approved by the US Food and Drug Administration for the treatment of agitation in adults with schizophrenia or bipolar disorder. The sublingual form of dexmedetomidine does not undergo first-pass hepatic metabolism, thus resulting in greater absorption than when ingested. In two Phase 3 studies of adults with schizophrenia or bipolar disorder, sublingual dexmedetomidine significantly reduced acute agitation at 2 hours, as measured by the five-item Positive and Negative Syndrome Scale-Excited Component (PEC). When initially appraising the potential utility of a new medication, number needed to treat (NNT) and needed to harm (NNH) can be helpful to assess the size of the treatment effect and, hence, clinical relevance.
ObjectiveCalculation of NNT and NNH through post hoc analysis of Phase 3 data.
MethodsPost hoc analysis of data were performed on data from two double-blind, randomized, placebo-controlled studies of sublingual dexmedetomidine in adults with schizophrenia or bipolar disorder experiencing acute agitation. Patients were randomized to a single dose of sublingual dexmedetomidine 180 μg, 120 μg, or placebo. The primary endpoint was mean change from baseline in the PEC total score. A therapeutic response was defined as a ≥40% reduction from baseline in PEC total score at 2 hours. NNT was calculated for PEC response rate for sublingual dexmedetomidine versus placebo. NNH was calculated using the incidence of adverse events for sublingual dexmedetomidine versus placebo. Likelihood to be helped or harmed (LHH) was calculated as the ratio of NNH to NNT.
ResultsNNT (95% CI) was 3 (2, 3) for 180 mcg and 3 (3, 4) for 120 ug in patients with schizophrenia and 3 (2, 3) for 180 mcg and 4 (3, 6) for 120 ug in patients with bipolar disorder. NNH was greater than 10 for all AEs except somnolence, where NNH was 7 (5, 10) for all doses pooled from both studies. LLH values were greater than 1 for efficacy versus applicable tolerability outcomes in all cases.
ConclusionsThis post hoc analysis demonstrated favorable NNT and NNH values for sublingual dexmedetomidine. In all instances therapeutic response was encountered more frequently than any adverse event. These values compare favorably to similar analyses for other approved agents for the treatment of agitation associated with schizophrenia or bipolar disorder, including intramuscular and inhaled formulations.
FundingBioXcel Therapeutics, Inc.
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