scholarly journals A 6-month, Randomized, Placebo-controlled, Double Blind Trial of Ziprasidone Plus a Mood Stabilizer in Subjects With Bipolar I Disorder

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1 ◽  
Author(s):  
E. Vieta ◽  
C. Bowden ◽  
K. Ice ◽  
O. Gurtovaya ◽  
J. Schwartz ◽  
...  
Keyword(s):  
Maintenance Treatment ◽  
Mood Stabilizer ◽  
Adjunctive Treatment ◽  
Rank Test ◽  
Open Label ◽  
Double Blind ◽  
Bipolar I Disorder ◽  
Mood Episode ◽  
Bipolar Mania ◽  
Group 5

Background:The objective of this study was to evaluate the efficacy and safety of ziprasidone adjunctive to a mood stabilizer for the maintenance treatment of bipolar mania.Methods:Male and female subjects with bipolar I disorder with MRS 3 14 were enrolled. Subjects achieving ≥ 8 consecutive weeks of stability with open-label ziprasidone (80-160 mg/d) and lithium or divalproex were randomized into the 6-month double-blind maintenance period, to ziprasidone + mood stabilizer or placebo + mood stabilizer. The primary and key secondary end points were the time to intervention for a mood episode, and time to discontinuation for any reason, respectively. Inferential analysis was performed using a Kaplan-Meier product-limit estimator (Log-rank test).Results:127 and 112 subjects were randomized to and treated in the ziprasidone and placebo groups, respectively. The time to intervention for a mood episode was significantly different, favoring ziprasidone (p = 0.0104). 19.7% and 32.4% of ziprasidone and placebo subjects, respectively, required intervention for a mood episode. Time to discontinuation for any reason was significantly different (p = 0.0047), favoring ziprasidone. Among treatment-emergent adverse events occurring in the double-blind period, the only event occurring more frequently in the ziprasidone group than in the placebo group (≥ 5%) was tremor (6.3% vs 3.6%, respectively).Conclusions:These results demonstrate that ziprasidone is an effective, safe, and well-tolerated adjunctive treatment with a mood stabilizer for long-term maintenance treatment of bipolar mania.

Quetiapine or Lithium Versus Placebo for Maintenance Treatment of Bipolar I Disorder After Stabilization on Quetiapine

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1 ◽  
Author(s):  
W.A. Nolen ◽  
R.H. Weisler ◽  
A. Neijber ◽  
Å. Hellqvist ◽  
B. Paulsson
Keyword(s):  
Bipolar Disorder ◽  
Interim Analysis ◽  
Maintenance Treatment ◽  
Additional Benefit ◽  
Study Medication ◽  
Open Label ◽  
Double Blind ◽  
Bipolar I Disorder ◽  
Time To Recurrence ◽  
Positive Results

Purpose:Quetiapine combined with lithium or divalproex is an effective maintenance treatment for bipolar I disorder.1,2 This double-blind, randomized trial (D1447C00144) investigated quetiapine monotherapy as maintenance treatment.Methods:Adults experiencing manic, depressed, or mixed episodes of bipolar disorder received open-label quetiapine. Patients achieving stabilization (YMRS ≤12 and MADRS ≤12, 4 consecutive weeks) were randomized to continue quetiapine (300-800 mg/d) or to switch to placebo or lithium (target serum 0.6-1.2 mEq/L) for up to 104 weeks or recurrent mood event. The primary endpoint was time to recurrence of any mood event. The study was terminated when interim analysis provided positive results.Results:Of 2438 patients starting open-label quetiapine, 1226 (50.3%) were randomized to study medication with 1172 in the ITT population. Mean median quetiapine dose was 546 mg/d; mean median lithium serum level was 0.63 mEq/L. Time to recurrence of any mood event was longer for continued quetiapine versus switching to placebo (HR, 0.29; 95% CI, 0.23-0.38; P< 0.0001), for switching to lithium versus switching to placebo (HR, 0.46; 95% CI, 0.36-0.59; P< 0.0001), and for continued quetiapine versus switching to lithium (HR, 0.66; 95% CI, 0.49-0.88; P=0.005). Safety findings were consistent with known profiles.Conclusions:In patients stabilized on quetiapine, continued quetiapine significantly decreased time to recurrence of any mood event versus switching to placebo. Switching to lithium was also more effective than switching to placebo and conferred no additional benefit versus continuing quetiapine.Supported by funding from AstraZeneca Pharmaceuticals LP.

Adjunctive tianeptine treatment for bipolar disorder: A 24-week randomized, placebo-controlled, maintenance trial

2019 ◽  
Vol 33 (4) ◽  
pp. 502-510 ◽  
Author(s):  
Márcia Kauer-Sant’Anna ◽  
Benicio N Frey ◽  
Adam Fijtman ◽  
Ana C Loredo-Souza ◽  
Aroldo A Dargél ◽  
...  
Keyword(s):  
Maintenance Treatment ◽  
Rating Scale ◽  
Bipolar Depression ◽  
Biological Rhythms ◽  
Preliminary Evidence ◽  
Rank Test ◽  
Cognitive Effect ◽  
Open Label ◽  
Double Blind ◽  
Adult Intelligence Scale

Objective: The purpose of this study was to assess the efficacy and tolerability of tianeptine as an adjunctive maintenance treatment for bipolar depression. Methods: This is a multicenter double-blind randomized placebo-controlled maintenance trial of adjunctive tianeptine 37.5 mg/day. Participants ( n=161) had a Montgomery-Asberg Depression Rating Scale ⩾12 at entry. After eight weeks of open-label tianeptine treatment, those who responded to tianeptine ( n=69) were randomized to adjunctive tianeptine ( n=36) or placebo ( n=33) in addition to usual treatment. Kaplan-Meier estimates and the Mantel-Cox log-rank test were used to evaluate differences in time to intervention for a mood episode between the tianeptine and placebo groups. We also assessed overall functioning, biological rhythms, quality of life, rates of manic switch and serum brain-derived neurotrophic factor levels. Results: There were no differences between adjunctive tianeptine or placebo regarding time to intervention or depression scores in the 24-week double-blind controlled phase. Patients in the tianeptine group showed better performance in the letter-number sequencing subtest from the Wechsler Adult Intelligence Scale at the endpoint ( p=0.014). Tianeptine was well tolerated and not associated with higher risk for manic switch compared to placebo. Conclusion: Tianeptine was not more effective than placebo in the maintenance treatment of bipolar depression. There is preliminary evidence suggesting a pro-cognitive effect of tianeptine in working memory compared to placebo.

scholarly journals Aripiprazole once-monthly as maintenance treatment for bipolar I disorder: a 52-week, multicenter, open-label study

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Joseph R. Calabrese ◽  
Na Jin ◽  
Brian Johnson ◽  
Pedro Such ◽  
Ross A. Baker ◽  
...  
Keyword(s):  
Maintenance Treatment ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Bipolar I Disorder

scholarly journals 145 Incidence and Characteristics of Akathisia and Restlessness During Cariprazine Treatment for Bipolar I Disorder

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 292-292
Author(s):  
Leslie Citrome ◽  
Lakshmi N. Yatham ◽  
Mehul Patel ◽  
Willie R. Earley
Keyword(s):  
Adverse Events ◽  
Bipolar Depression ◽  
Partial Agonist ◽  
Fixed Dose ◽  
Double Blind ◽  
Study Objective ◽  
Bipolar I Disorder ◽  
Bipolar Mania ◽  
Post Hoc ◽  
Depressive Episodes

Abstract:Study Objective:Akathisia and restlessness are common adverse events associated with atypical antipsychotic use; in severe cases, symptoms may lead to treatment discontinuation. Cariprazine, a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, is approved for the treatment of schizophrenia (1.5–6 mg/d), and manic or mixed (3–6 mg/d) and depressive episodes (1.5–3 mg/d) associated with bipolar I disorder. Pooled post hoc analyses were conducted to characterize the incidence and severity of cariprazine-related akathisia and restlessness in patients who participated in bipolar disorder studies.Method:All studies were Phase II/III multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in patients with bipolar I disorder who were currently experiencing a manic/mixed (NCT00488618, NCT01058096, NCT01058668) or depressive (NCT01396447, NCT02670538, NCT02670551) mood episode. Patients received flexibly dosed cariprazine 3-12 mg/d (day 1: 1.5 mg; day 2: 3 mg; subsequent up-titration in 3-mg increments if needed) or placebo in the bipolar mania studies and fixed-dose cariprazine 1.5 mg/d, 3 mg/d (slow titration to 1.5 mg [day 8] and 3 mg [day 15] or initiation at 1.5 mg with escalation to 3 mg on day 15), or placebo in the bipolar depression studies. The incidence, severity, and timing of treatment-emergent adverse events (TEAEs) of akathisia and restlessness were evaluated in this analysis.Results:In the bipolar mania studies (N=1065), TEAEs of akathisia occurred in 20.2% of cariprazine-treated patients and 4.8% of placebo-treated patients; 2.4% of cariprazine-treated patients discontinued due to akathisia. TEAEs of restlessness occurred in 6.7% and 2.3% of cariprazine- and placebo-treated patients, respectively, and caused discontinuation of 0.3% of cariprazine-treated patients. In the bipolar depression studies (N=1407), akathisia occurred in 2.1%, 5.5%, and 9.6% of patients in the placebo, cariprazine 1.5 mg/d, and cariprazine 3 mg/d groups, respectively; <2% of patients in each group discontinued due to akathisia. Restlessness occurred in 3.2% of placebo-treated patients and 2.1% and 6.6% of patients in the 1.5 and 3 mg/d groups, respectively; discontinuations due to restlessness occurred in 0.2% and 1.1% of patients in the 1.5 and 3 mg/d groups. Akathisia and restlessness in cariprazine-treated patients was generally mild or moderate in severity (>92% in both populations). Most akathisia events in the bipolar mania studies were reported for the first time within the first 2-3 weeks of treatment.Conclusions:In these post hoc analyses, the incidence of akathisia and restlessness were generally higher with cariprazine than with placebo. However, most incidences were mild or moderate in severity, and infrequently led to discontinuation. Akathisia appears to be dose related in both mania and depression, suggesting lower doses and slower titration may reduce occurrence.Funding Acknowledgements:Allergan plc.

Recurrence rates in stable bipolar disorder patients after drug discontinuation v. drug maintenance: a systematic review and meta-analysis

2020 ◽  
pp. 1-9
Author(s):  
Taro Kishi ◽  
Yuki Matsuda ◽  
Kenji Sakuma ◽  
Makoto Okuya ◽  
Kazuo Mishima ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Recurrence Rate ◽  
Meta Analysis ◽  
Mood Stabilizer ◽  
Recurrence Risk ◽  
Drug Discontinuation ◽  
Recurrence Rates ◽  
Double Blind ◽  
Mood Episode ◽  
Depressive Episodes

Abstract Background This random-effects model meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups. Methods We conducted systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. We calculated risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH). Primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. We also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months. Results We identified 22 studies (n = 5462) receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. Mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs (95% confidence interval, NNTB/NNTH) of recurrence rate at 6 months were 0.61 (0.54–0.70, 5) for any mood episode, 0.72 (0.60–0.87, 13) for depressive episodes, and 0.45 (0.36–0.57, 6) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (0.61–0.82, 6). Conclusions Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.

scholarly journals Ziprasidone with adjunctive mood stabilizer in the maintenance treatment of bipolar I disorder: Long-term changes in weight and metabolic profiles

2012 ◽  
Vol 22 (2) ◽  
pp. 123-131 ◽  
Author(s):  
David E. Kemp ◽  
Onur N. Karayal ◽  
Joseph R. Calabrese ◽  
Gary S. Sachs ◽  
Elizabeth Pappadopulos ◽  
...  
Keyword(s):  
Maintenance Treatment ◽  
Mood Stabilizer ◽  
Metabolic Profiles ◽  
Bipolar I Disorder ◽  
Long Term Changes

Randomized, double-blind, phase 3 trial of first-line pembrolizumab + platinum doublet chemotherapy (chemo) ± lenvatinib in patients (pts) with metastatic nonsquamous non–small-cell lung cancer (NSCLC): LEAP-006.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS9118-TPS9118 ◽  
Author(s):  
Rina Hui ◽  
Makoto Nishio ◽  
Martin Reck ◽  
Delvys Rodriguez-Abreu ◽  
Tamer M. Fouad ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitor ◽  
Tumor Imaging ◽  
Growth Factor Receptors ◽  
Rank Test ◽  
Fibroblast Growth Factor Receptors ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind

TPS9118 Background: Lenvatinib (multiple-receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptors α, c-kit, and RET) has antitumor activity in combination with pembrolizumab (anti–PD-1 inhibitor) or with chemo in advanced NSCLC. LEAP-006 (NCT03829319) evaluates first-line lenvatinib with pembrolizumab + chemo for metastatic nonsquamous NSCLC. Methods: This randomized, double-blind, 2-part, phase 3 study enrolls pts ≥18 years with histologically/cytologically confirmed metastatic, nonsquamous, treatment-naive NSCLC without sensitizing genetic aberrations. Pts receive lenvatinib 8 mg daily or matching placebo + pembrolizumab 200 mg + pemetrexed 500 mg/m2 + carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 Q3W (4 cycles) followed by maintenance pembrolizumab (35 cycles) + lenvatinib/placebo + pemetrexed (no limit). In part 1 (open-label safety run-in), ~12 pts receive lenvatinib + pembrolizumab + chemo (n ≥6 in each chemo arm). If < 3 dose-limiting toxicities (DLTs; select prespecified AEs) occur in 6 pts in each arm in cycle 1, part 2 will begin enrolling. If ≥3 DLTs occur in 6 pts in each arm, enrollment in part 1 may continue with advisement by the study oversight committee. In part 2, pts are randomized 1:1 to lenvatinib or placebo + pembrolizumab + chemo, stratified by PD-L1 tumor proportion score ( < 50%/≥50%), geographic site (East Asian/other), and ECOG PS (0/1). Tumor imaging occurs at baseline and Q6W until wk 18; then Q9W until wk 54; then Q12W until verified PD, initiation of new cancer therapy, study withdrawal, or death. AEs are graded by NCI CTCAE v4.0. The primary endpoint in part 1 is safety. The primary endpoints in part 2 are PFS (RECIST v1.1 by BICR) and OS, analyzed by Kaplan-Meier method and stratified log-rank test. Secondary endpoints in part 2 are ORR and DOR (RECIST v1.1 by BICR), safety, and quality of life. Enrollment into part 1 will begin in March 2019. For part 2, approximately 714 pts will enroll in 160 sites in 17 countries. Clinical trial information: NCT03829319.

scholarly journals 056 Efficacy and safety of the Bruton’s tyrosine kinase inhibitor evobrutinib (M2951) in patients with relapsing multiple sclerosis over 48 weeks: a randomized, placebo-controlled, phase 2 study

2019 ◽  
Vol 90 (e7) ◽  
pp. A18.2-A19
Author(s):  
Xavier Montalban ◽  
Douglas L Arnold ◽  
Martin S Weber ◽  
Ivan Staikov ◽  
Karolina Piasecka-Stryczynska ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Dimethyl Fumarate ◽  
Rank Test ◽  
Bruton’S Tyrosine Kinase ◽  
Phase 2 ◽  
Open Label ◽  
Double Blind ◽  
Bruton's Tyrosine Kinase ◽  
Phase 2 Study

IntroductionEvobrutinib (M2951) is a highly specific oral inhibitor of Bruton’s tyrosine kinase, a key regulator of B cell and macrophage functions implicated in MS.MethodsIn this double-blind, phase 2 study (NCT02975349), adult patients (≤65 years) with relapsing MS (RMS) were randomized to evobrutinib 25 mgQD, 75 mgQD, 75 mgBID, placebo, or open-label dimethyl fumarate (240 mgBID; reference arm) for 48 weeks; placebo-treated patients switched to evobrutinib 25 mgQD after 24 weeks. The primary endpoint was the total number of T1 gadolinium-enhancing (T1Gd+) lesions at Weeks 12, 16, 20, and 24. Secondary endpoints included annualized relapse rate (ARR), MRI measures at Weeks 24 and 48, and safety.ResultsAmong 261 patients, the sum of T1Gd+ lesions over Weeks 12–24 was reduced with evobrutinib 75 mgQD (p=0.002) and 75 mgBID (p=0.03); a dose response was observed (p=0.001). There was no evidence of change in effect on T1Gd+ lesions (mean±SD; Wilcoxon signed-rank test) between Weeks 24 and 48 with evobrutinib 75 mgQD (0.28±0.91 to 0.85±2.87; p=0.57) or 75 mgBID (0.24±0.88 to 0.49±1.22; p=0.23). ARR (unadjusted [95%CI]) was 0.25 (0.12–0.44) for evobrutinib 75 mgQD and 0.11 (0.04–0.25) for 75 mgBID over 48 weeks, and 0.37 (0.17–0.70) for placebo over 24 weeks. Evobrutinib appeared well-tolerated. Shifts to Grade 3–4 ALT and AST elevations from normal (grade 0) occurred in 8 (5.4%) and 6 (3.9%) evobrutinib-treated patients respectively, driven by events with onset within the first 24 weeks.ConclusionsEvobrutinib is the first BTK inhibitor to demonstrate disease activity reduction in RMS. The observed benefit-risk profile supports further clinical development.

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