Evaluating the impact of a Risk Evaluation and Mitigation Strategy with tolvaptan to monitor liver safety in patients with autosomal dominant polycystic kidney disease.

Background: On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data.

Methods: This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021).

Efficacy, Safety, and Tolerability of Centanafadine Sustained-Release Tablets in Adults With Attention-Deficit/Hyperactivity Disorder: Results of 2 Phase 3, Randomized, Double-blind, Multicenter, Placebo-Controlled Trials.

Purpose/background: Centanafadine is an inhibitor of norepinephrine, dopamine, and serotonin reuptake transporters under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD).

Methods/procedures: Two phase 3 randomized, double-blind, placebo-controlled, parallel-group studies of 200 mg/d or 400 mg/d centanafadine sustained-release tablets versus placebo included adults (18-55 years of age) with a diagnosis of ADHD. The primary and key secondary efficacy endpoints were the change from baseline at day 42 in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score and the Clinical Global Impression-Severity of Illness Scale, respectively.

Discovery research and development history of the dopamine D receptor partial agonists, aripiprazole and brexpiprazole.

Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify ).

An open-label, positron emission tomography study of the striatal D/D receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

Purpose: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D/D receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg.

Methods: Occupancy was measured at 4 and 23.

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials.

Objective: To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD).

Design: Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258).

Setting: Study 1: 81 sites in 7 countries.

A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Adjunctive Therapy in Adults With Major Depressive Disorder.

Background: Long-term treatment is recommended in major depressive disorder (MDD) to prevent relapse and to restore functioning. The aim of this study (Orion; NCT01360866) was to assess the long-term safety, tolerability, and efficacy of open-label treatment with adjunctive brexpiprazole in adult patients with MDD.

Methods: Patients rolled over into this 52-week study (amended to 26 weeks) from 3 randomized, double-blind, placebo-controlled studies.

The safety and tolerability of aripiprazole once-monthly as maintenance treatment for bipolar I disorder: A double-blind, placebo-controlled, randomized withdrawal study.

Background: Aripiprazole once-monthly 400 mg (AOM 400), an atypical long-acting injectable antipsychotic, has demonstrated efficacy and safety in maintenance treatment of bipolar I disorder (BP-I). We further assess safety and tolerability and characterize adverse events (AEs) across the duration of aripiprazole exposure.

Methods: Patients with BP-I were stabilized on oral aripiprazole (2-8 weeks), AOM 400 (12-28 weeks), followed by 1:1 randomization of patients meeting stability criteria to a 52-week, double-blind, placebo-controlled withdrawal phase.

The effects of brexpiprazole and aripiprazole on body weight as monotherapy in patients with schizophrenia and as adjunctive treatment in patients with major depressive disorder: an analysis of short-term and long-term studies.

The aim of this analysis was to explore the effects of brexpiprazole and aripiprazole on body weight when used as monotherapy to treat schizophrenia and as adjunctive treatment to antidepressant treatment (ADT) for major depressive disorder (MDD) in short-term (4/6 weeks) and long-term (≤52 weeks) studies. Body weight data were obtained from the clinical studies of each drug (brexpiprazole and aripiprazole), in schizophrenia and adjunctive treatment of MDD. Data were pooled and analyzed to assess the mean change in body weight and to determine the incidence of a clinically relevant change in body weight from baseline (≥7% increase or decrease, at any time) in each treatment group.

A Randomized, Placebo-Controlled Study of the Efficacy and Safety of Fixed-Dose Brexpiprazole 2 mg/d as Adjunctive Treatment of Adults With Major Depressive Disorder.

Objective: To assess the efficacy, safety, and tolerability of brexpiprazole as adjunct to antidepressant treatment (ADT) in adults with major depressive disorder (MDD) and inadequate response to ADTs.

Methods: Outpatients with inadequate response to 1-3 ADTs during their current depressive episode (DSM-IV-TR criteria) were administered prospective, open-label ADT. Those patients with inadequate response to prospective ADT were randomized to double-blind, adjunctive brexpiprazole 2 mg/d or placebo.

Efficacy and safety of flexibly dosed brexpiprazole for the adjunctive treatment of major depressive disorder: a randomized, active-referenced, placebo-controlled study.

Objective: To assess the efficacy, safety, and tolerability of brexpiprazole as adjunctive treatment in adults with major depressive disorder (MDD) and an inadequate response to prior antidepressant treatment (ADT).

Methods: Patients with a current major depressive episode after prior treatment with 1-3 ADTs entered an 8- or 10-week prospective treatment phase in which they received double-blind placebo adjunct to open-label ADT. Inadequate responders were randomized (2:2:1) to brexpiprazole 2-3 mg/day, placebo, or quetiapine extended-release (XR) 150-300 mg/day, adjunct to the same ADT, for 6 weeks.

Symptoms and functioning with aripiprazole once-monthly injection as maintenance treatment for bipolar I disorder.

Background: Effects of maintenance treatment with aripiprazole once-monthly 400mg (AOM 400) on symptoms and functioning were assessed in adults with bipolar I disorder (BP-I) after a manic episode.

Methods: Patients were stabilized on oral aripiprazole, cross-titrated to AOM 400, then randomized in a 52-week, double-blind, placebo-controlled, withdrawal phase. Prespecified secondary outcomes are reported: time to hospitalization for mood episode, Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression-Bipolar scale, Functioning Assessment Short Test (FAST), and Brief Quality of Life in Bipolar Disorder questionnaire.

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

Background: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown.

Methods: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial.

Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain.

Context: Prior Phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.

Objectives: To assess adjunctive nabiximols (Sativex), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol [27 mg/mL] and cannabidiol [25 mg/mL]), in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.

Methods: Phase 3, double-blind, randomized, placebo-controlled trial in patients with advanced cancer and average pain Numerical Rating Scale scores ≥4 and ≤8 despite optimized opioid therapy.

Oral Aripiprazole as Maintenance Treatment in Adolescent Schizophrenia: Results From a 52-Week, Randomized, Placebo-Controlled Withdrawal Study.

Objective: To evaluate the efficacy, safety, and tolerability of aripiprazole, a dopamine D receptor partial agonist, as maintenance treatment in adolescent outpatients with schizophrenia.

Method: This was a multicenter, double-blind, placebo-controlled, randomized withdrawal design trial. Participants 13 to 17 years of age with a diagnosis of schizophrenia (DSM-IV-TR) were first cross-titrated from their other oral antipsychotic(s) (4-6 weeks), then stabilized (7-21 weeks) on oral aripiprazole 10 to 30 mg/d, and finally randomized 2:1 to continuation of oral aripiprazole or to placebo in a double-blind maintenance phase (≤52 weeks).

Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies.

Background: Opioids are critical for managing cancer pain, but may provide inadequate relief and/or unacceptable side effects in some cases.

Objective: To assess the analgesic efficacy of adjunctive Sativex (Δ-tetrahydrocannabinol (27 mg/mL): cannabidiol (25 mg/mL)) in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.

Methods: This report describes two phase 3, double-blind, randomized, placebo-controlled trials.

Randomized, Double-Blind, Placebo-Controlled Trial Demonstrates the Efficacy and Safety of Oral Aripiprazole for the Treatment of Tourette's Disorder in Children and Adolescents.

Objectives: Aripiprazole modulates dopaminergic and serotonergic pathways that may play a role in the pathogenesis of Tourette's disorder (TD). This trial evaluated the efficacy and safety of oral aripiprazole in the suppression of tics in children and adolescents with TD.

Methods: This phase 3, randomized, double-blind, placebo-controlled trial ( ClinicalTrials.

Aripiprazole Once-Monthly in the Treatment of Acute Psychotic Episodes in Schizophrenia: Post Hoc Analysis of Positive and Negative Syndrome Scale Marder Factor Scores.

Background: Long-acting injectable antipsychotics are treatment options for acute and long-term treatment of patients with schizophrenia. In a previously published 12-week randomized, double-blind, placebo-controlled clinical trial of patients with schizophrenia experiencing an acute psychotic episode, aripiprazole once-monthly 400 mg (AOM 400) produced significantly greater improvement than placebo on the primary endpoint, Positive and Negative Syndrome Scale (PANSS) total score at week 10.

Methods: To examine the efficacy of AOM 400 across a broader representation of schizophrenia symptoms, including agitation, a post hoc analysis of this trial was carried out to assess the change in PANSS Marder factor domains (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression) and the PANSS excited component (equivalent to Marder factor domain uncontrolled hostility/excitement plus the tension item) by comparing differences in change from baseline between AOM 400 and placebo using a mixed model for repeated measures.

Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration.

Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia.

Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466).

Efficacy and Safety of Aripiprazole Once-Monthly in the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled, 52-Week Randomized Withdrawal Study.

Objective: To evaluate efficacy, safety, and tolerability of long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) as maintenance treatment for bipolar I disorder (BP-I).

Methods: In a double-blind, placebo-controlled, 52-week randomized withdrawal study conducted from August 2012 to April 2016, patients with a DSM-IV-TR diagnosis of BP-I currently experiencing a manic episode were stabilized sequentially on oral aripiprazole and AOM 400 and then randomized to AOM 400 or placebo. The primary end point was time from randomization to recurrence of any mood episode.

Efficacy and Safety of Brexpiprazole (OPC-34712) as Maintenance Treatment in Adults with Schizophrenia: a Randomized, Double-Blind, Placebo-Controlled Study.

Background: Brexpiprazole has previously demonstrated efficacy in acute schizophrenia trials. The objective of this trial was to assess the efficacy, safety, and tolerability of maintenance treatment with brexpiprazole in adults with schizophrenia.

Methods: Patients with an acute exacerbation of psychotic symptoms were converted to brexpiprazole (1-4mg/d) over 1 to 4 weeks and entered a single-blind stabilization phase.

Effects of aripiprazole once-monthly on symptoms of schizophrenia in patients switched from oral antipsychotics.

Objective: To assess the effects of aripiprazole once-monthly 400 mg (AOM 400) on clinical symptoms and global improvement in schizophrenia after switching from an oral antipsychotic.

Methods: In a multicenter, open-label, mirror-image, naturalistic study in patients with schizophrenia (>1 year, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] criteria), changes in efficacy measures were assessed during prospective treatment (6 months) with AOM 400 after switching from standard-of-care oral antipsychotics. During prospective treatment, patients were cross-titrated to oral aripiprazole monotherapy (1-4) weeks followed by open-label AOM 400 (24 weeks).

Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study.

Objective: To evaluate efficacy, safety, and tolerability of brexpiprazole adjunctive to antidepressant treatments (ADTs) in patients with major depressive disorder (as defined by DSM-IV-TR criteria) with inadequate response to ADTs.

Method: Patients still depressed despite 1-3 prior ADTs followed by 8 weeks of prospective physician-determined, open-label ADT were randomized (1:1:1) to double-blind brexpiprazole 3 mg/d, brexpiprazole 1 mg/d, or placebo for 6 weeks. The primary efficacy end point was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 6.