Efficacy and safety of brexpiprazole in schizophrenia: Meta-analysis of three double-blind, randomized, placebo-controlled phase 3 studies

2016 ◽  
Vol 33 (S1) ◽  
pp. S109-S109 ◽  
Author(s):  
C. Weiss ◽  
P. Zhang ◽  
M.J. Hakala ◽  
A. Skuban ◽  
E. Weiller
Keyword(s):  
Partial Agonist ◽  
Meta Analysis ◽  
Placebo Treatment ◽  
Phase 3 ◽  
Double Blind ◽  
Treatment Groups ◽  
Acute Schizophrenia ◽  
Three Phase ◽  
Flexible Dosing ◽  
Competing Interest

IntroductionBrexpiprazole is a serotonin-dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors.ObjectivesTo evaluate the efficacy, safety, and tolerability of brexpiprazole in patients with acute schizophrenia in a meta-analysis of three phase 3 studies with brexpiprazole.AimThe primary endpoint was change from baseline to week 6 in PANSS total score.MethodsData from the 3 clinical studies in patients with acute schizophrenia were combined and analyzed using individual patient data meta-analysis. In two similarly designed studies (NCT01396421; NCT01393613), patients with acute schizophrenia were randomized to fixed-doses of brexpiprazole 2 mg/day, 4 mg/day or placebo (a low-dose treatment group was included in each study [0.25 mg and 1.0 mg]; not included in the meta-analysis). In the third study (NCT01810380), patients were randomized to flexible dosing of brexpiprazole (2 to 4 mg/day), placebo, or an active reference (quetiapine extended release). Changes from baseline for brexpiprazole vs. placebo were analyzed using an MMRM approach.ResultsBrexpiprazole 2–4 mg (n = 868) was superior to placebo (n = 517) in change from baseline in PANSS total score (−20.1 vs. −14.3; estimated treatment difference to placebo: −5.8 [95% CI: −8.0; −3.6]; P < 0.001). The proportions of patients reporting TEAEs were similar between the brexpiprazole and placebo treatment groups (57.9% vs. 57.5%). No unexpected safety concerns were observed.ConclusionThis meta-analysis supports evidence from three individual trials that brexpiprazole is efficacious and safe in treating patients with acute schizophrenia.Disclosure of interestThe authors have not supplied their declaration of competing interest.

An interventional, multi-center, randomized, double-blind, placebo-controlled, active reference, flexible dose study of brexpiprazole in adults with acute schizophrenia

2016 ◽  
Vol 33 (S1) ◽  
pp. S99-S99 ◽  
Author(s):  
S.R. Marder ◽  
M. Hakala ◽  
M. Gislum ◽  
A. Skuban ◽  
E. Weiller ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Partial Agonist ◽  
Statistical Significance ◽  
Placebo Treatment ◽  
Sensitivity Analyses ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Double Blind Placebo ◽  
Acute Schizophrenia ◽  
The Difference

IntroductionBrexpiprazole is a serotonin-dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors.ObjectivesEvaluating the efficacy, safety, and tolerability of flexible doses of brexpiprazole compared with placebo in patients with acute schizophrenia.AimPrimary endpoint was change from baseline to week 6 in PANSS total score and key secondary endpoint was change from baseline to week 6 in CGI-S score.MethodsPhase 3, multi-center, randomized, double-blind, placebo-controlled, active reference, trial (NCT01810380). Hospitalized patients were randomized to brexpiprazole (2 to 4 mg/day), placebo, or quetiapine extended release (400 to 800 mg/day) for 6 weeks. Quetiapine was included as an active reference. Changes from baseline were analyzed using an MMRM approach.ResultsMean change in PANSS total score was −20.0 and −15.9 in the brexpiprazole (n = 150) and placebo (n = 159) groups, respectively (P = 0.056). Sensitivity analyses suggested treatment effect (e.g., ANCOVA, LOCF: P = 0.025; ANCOVA, OC: P = 0.026). Mean change in PANSS total score (−24.0) with quetiapine (n = 150) was significantly greater than that with placebo (P < 0.001), demonstrating sensitivity of the assay. Brexpiprazole separated from placebo on the mean change in CGI-S score (−1.2 vs. −0.9, P = 0.014). The proportion of patients reporting TEAEs were similar between the brexpiprazole and placebo treatment groups (54% versus 54.7%).ConclusionTreatment with brexpiprazole showed a clinically meaningful improvement in patients with acute schizophrenia. While the difference between brexpiprazole and placebo only approached statistical significance, sensitivity analyses and secondary endpoints supported a treatment effect of brexpiprazole.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals EXPRESS: Efficacy and Safety of Tadalafil in a Pediatric Population with Pulmonary Arterial Hypertension: Phase 3 randomized, Double Blind Placebo-Controlled Study

2021 ◽  
pp. 204589402110249
Author(s):  
David D Ivy ◽  
Damien Bonnet ◽  
Rolf MF Berger ◽  
Gisela Meyer ◽  
Simin Baygani ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Statistical Significance ◽  
Significance Testing ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Statistical Significance Testing ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Treatment Groups ◽  
Pulmonary Arterial

Objective: This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension (PAH). Methods: This phase-3, international, randomized, multicenter (24 weeks double-blind placebo controlled period; 2-year, open-labelled extension period), add-on (patient’s current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with PAH. Patients received tadalafil 20 mg or 40 mg based on their weight (Heavy-weight: ≥40 kg; Middle-weight: ≥25—<40 kg) or placebo orally QD for 24 weeks. Primary endpoint was change from baseline in 6-minute walk (6MW) distance in patients aged ≥6 years at Week 24. Sample size was amended from 134 to ≥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results: Patient demographics and baseline characteristics (N=35; tadalafil=17; placebo=18) were comparable between treatment groups; median age was 14.2 years (6.2 to 17.9 years) and majority (71.4%, n=25) of patients were in HW cohort. Least square mean (SE) changes from baseline in 6MW distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 [20.41] vs 36.60 [20.78] meters; placebo-adjusted mean difference [SD] 23.88 [29.11]). Safety of tadalafil treatment was as expected without any new safety concerns. During study period 1, two patients (1 in each group) discontinued due to investigator’s reported clinical worsening, and no deaths were reported. Conclusions: The statistical significance testing was not performed between the treatment groups due to low sample size, however, the study results show positive trend in improvement in non invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with PAH. Safety of tadalafil treatment was as expected without any new safety signals.

scholarly journals Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson’s disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The ‘Exenatide-PD3’ study

BMJ Open ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. e047993
Author(s):  
Nirosen Vijiaratnam ◽  
Christine Girges ◽  
Grace Auld ◽  
Marisa Chau ◽  
Kate Maclagan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Primary Outcome ◽  
Phase 3 ◽  
Double Blind ◽  
Treatment Groups ◽  
Link Type ◽  
South Central ◽  
Disease Modifying ◽  
Secondary Outcomes

IntroductionParkinson’s disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure.Methods and analysisThis is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences.Ethics and disseminationThis trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format.Trial registration numbersNCT04232969, ISRCTN14552789.

scholarly journals Efficacy and tolerability of the investigational topical cream SD-101 (6% allantoin) in patients with epidermolysis bullosa: a phase 3, randomized, double-blind, vehicle-controlled trial (ESSENCE study)

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Amy S. Paller ◽  
◽  
John Browning ◽  
Milos Nikolic ◽  
Christine Bodemer ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Wound Closure ◽  
Trial Registration ◽  
Controlled Study ◽  
Phase 3 ◽  
Double Blind ◽  
Treatment Groups ◽  
Topical Cream ◽  
Link Type ◽  
Total Body

Abstract Background Epidermolysis bullosa (EB) is a rare genetic disorder that manifests as blistering and/or skin erosion. There is no approved treatment for EB; current standard of care consists of wound and pain management. SD-101 6% is a topical cream containing 6% allantoin that was developed for treating skin lesions in patients with EB. The aim of this phase 3, multicenter, randomized, double-blind, vehicle-controlled study was to assess the efficacy and safety of SD-101 6% cream versus vehicle (0% allantoin) on lesions in patients with EB. Methods Eligible patients were ≥1 month old, had a diagnosis of EB (simplex, recessive dystrophic, or intermediate junctional) and a target wound 10–50 cm2 in size that was present for ≥21 days. Patients were randomly assigned to SD-101 6% cream or vehicle, which was applied topically once a day to the entire body for 3 months. Primary efficacy endpoints were time to complete target wound closure within 3 months and the proportion of patients who experienced complete target wound closure within 3 months. Post hoc subgroup analyses were conducted by patient age and in those with body surface area index of total body wound burden ≥5% at baseline. Results In total, 169 patients were enrolled and randomly assigned to SD-101 6% (n = 82) or vehicle (n = 87). Baseline demographics and disease characteristics were similar between treatment groups. There were no statistically significant differences between treatment groups in time to target wound closure (hazard ratio, 1.004; 95% confidence interval [CI] 0.651, 1.549; P = 0.985) or proportion of patients with complete target wound closure within 3 months (odds ratio [95% CI], 0.733 [0.365, 1.474]; nominal P = 0.390). A positive trend toward faster wound closure with SD-101 6% versus vehicle was observed in patients aged 2 to <12 years and those with total body wound burden ≥5% at baseline. SD-101 6% cream was well tolerated. Conclusions SD-101 6% cream for treatment of EB-associated lesions was not more effective than vehicle in shortening the time to complete target wound closure or achieving complete target wound closure within 3 months. Trial registration ClinicalTrials.gov, NCT02384460; Date of trial registration, February 13, 2015; First participant enrolled, March 11, 2015.

scholarly journals P216 Effects of filgotinib on anaemia, thrombocytopoenia and leukopoenia: results from a Phase 3 study in patients with active RA and prior inadequate response or intolerance to bDMARDs

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
David Walker ◽  
Mark C Genovese ◽  
Kenneth Kalunian ◽  
Jacques-Eric Gottenberg ◽  
Beatrix Bartok ◽  
...  
Keyword(s):  
Janus Kinase ◽  
Stock Ownership ◽  
Inadequate Response ◽  
Phase 3 ◽  
Double Blind ◽  
Treatment Groups ◽  
Normal Platelet ◽  
Haematopoietic Growth Factor ◽  
Baseline Haemoglobin ◽  
Low Levels

Abstract Background Cytopoenias are common in patients treated for rheumatoid arthritis (RA) with non-janus kinase 1 (JAK1)-selective inhibitors, possibly due to JAK2-mediated haematopoietic growth factor inhibition. We investigated the extent of cytopoenia in patients with active RA, despite prior treatment with biological disease-modifying antirheumatic drugs (bDMARDs), treated with the JAK1-selective inhibitor filgotinib (FIL), in a Phase 3 trial (FINCH2; NCT02873936). Methods In the double-blind, Phase 3 FINCH2 trial, patients were randomised 1:1:1 to receive oral FIL 200mg, 100mg, or placebo (PBO) once daily for 24 weeks (W) + conventional synthetic DMARDs. We assessed shifts from baseline at 12 and 24 weeks in haemoglobin, platelets, neutrophils and lymphocytes. Results 448 patients were treated: FIL 200mg, n = 147; FIL 100mg, n = 153; PBO, n = 148. Overall, haemoglobin, platelet, lymphocyte and neutrophil levels remained consistent throughout the study. At baseline, 129 (28.8%), 4 (0.9%), 10 (2.2%) and 26 (5.8%) patients had mild-moderate low levels of haemoglobin, platelets, neutrophils and lymphocytes, respectively, and 5 (1.1%) had severely low levels of lymphocytes. Of the patients with mild-moderate low haemoglobin levels at baseline, 10-13% achieved normal levels by W24 vs 8% receiving PBO (Table). Of those with normal baseline haemoglobin levels, 6-10% had mild low levels at W24. All patients with baseline mild-moderate low platelets and neutrophils had normal levels at W24, except one patient with mild neutropoenia receiving FIL 100mg. Of the patients with normal platelet and neutrophil levels at baseline, &gt;94% maintained these at W24 in all treatment groups. By W24, 3.2%, 5.2% and 2.2% of patients treated with FIL 200mg, FIL 100mg and PBO, respectively in the baseline mild-moderate subgroup and 1.7% in the severe subgroup treated with FIL 100mg had normal lymphocyte counts. Conclusion In this study, most patients in the baseline normal cell count subgroups maintained this status over 24 weeks of FIL treatment. Of the patients with mild-to-moderately low haemoglobin at baseline, &gt;9% shifted towards haemoglobin normalisation. Similar patterns of improvement from baseline were observed for platelet, lymphocyte and neutrophil counts. FIL appears not to increase the incidence of cytopenias in patients with active RA despite prior biologic therapies. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis, Roche. M.C. Genovese: Other; Received support from Gilead Sciences Inc., Galapagos NV, AbbVie Inc. Eli Lilly and Company, Pfizer. K. Kalunian: Grants/research support; Grand support from Gilead. J. Gottenberg: None. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Tan: Corporate appointments; Employee of Gilead Sciences, Inc... Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Other; Employee of Galapagos. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. K. de Vlam: None. T. Takeuchi: None.

scholarly journals Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
David H. Adams ◽  
Lu Zhang ◽  
Brian A. Millen ◽  
Bruce J. Kinon ◽  
Juan-Carlos Gomez
Keyword(s):  
Weight Gain ◽  
Adverse Events ◽  
Term Treatment ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Treatment Groups ◽  
Long Term Treatment ◽  
Blind Comparison

We tested the hypothesis that long-term treatment with pomaglumetad methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either pomaglumetad methionil (n=516) or aripiprazole (n=162). Treatment groups were also compared on efficacy and various safety measures, including serious adverse events (SAEs), discontinuation due to adverse events (AEs), treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (EPS), and suicide-related thoughts and behaviors. The pomaglumetad methionil group showed significantly greater weight loss at Week 24 (Visit 12) compared with the aripiprazole group (−2.8 ± 0.4 versus 0.4 ± 0.6;P<0.001). However, change in Positive and Negative Syndrome Scale (PANSS) total scores for aripiprazole was significantly greater than for pomaglumetad methionil (−15.58 ± 1.58 versus −12.03 ± 0.99;P=0.045). The incidences of SAEs (8.2% versus 3.1%;P=0.032) and discontinuation due to AEs (16.2% versus 8.7%;P=0.020) were significantly higher for pomaglumetad methionil compared with aripiprazole. No statistically significant differences in the incidence of TEAEs, EPS, or suicidal ideation or behavior were noted between treatment groups. In conclusion, long-term treatment with pomaglumetad methionil resulted in significantly less weight gain than aripiprazole. This trial is registered with ClinicalTrials.govNCT01328093.

scholarly journals 110. A Phase 3, Multicenter, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infections

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S67-S68
Author(s):  
Yihong Sun ◽  
Jia Fan ◽  
Gang Chen ◽  
Xiaofei Chen ◽  
Xiaoling Du ◽  
...  
Keyword(s):  
Clinical Cure ◽  
Additional Treatment ◽  
Double Blind Study ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Study Drug Administration ◽  
Treatment Groups ◽  
Secondary Endpoints ◽  
Abdominal Infections

Abstract Background In China, the prevalence of infections due to multidrug-resistant gram-negative bacteria is high and additional treatment options for complicated intra-abdominal infections (cIAI) are needed. This study compared the efficacy and safety of ceftolozane/tazobactam (C/T) + metronidazole (MTZ) versus meropenem (MEM) + placebo (pbo) for the treatment of cIAI in adult Chinese participants. Methods This was a phase 3, double-blind study conducted at 21 centers in China (NCT03830333). Participants aged 18-75 years with cIAI requiring surgical intervention within 24 hours of study drug administration were stratified by site of infection and randomized 1:1 to receive 1.5 g C/T (1 g ceftolozane and 0.5 g tazobactam) + 0.5 g MTZ administered intravenously (IV) every 8 hours (q8h) or 1 g MEM + pbo administered IV q8h for 4-14 days. The primary endpoint was clinical cure at test of cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included rates of clinical cure, per-participant microbiologic response, per-pathogen microbiologic response, and adverse events (AE). Non-inferiority for clinical cure at TOC in the CE population was confirmed if the lower bound of the 2-sided 95% CI for the between-treatment difference in the clinical cure rate was larger than −12.5%. Results A total of 134 participants were randomized to each treatment group. Demographics and baseline characteristics were generally well balanced between treatment groups (Table 1). The median (range) age in the ITT population was 50 (18-75) years and 61% were men. The most frequent sites of infection were the appendix (C/T + MTZ, 50.0%; MEM + pbo, 49.3%) and gallbladder (C/T + MTZ, 27.6%; MEM + pbo, 29.1%). Overall, the most frequently isolated pathogens were Escherichia coli (61.4%) and Klebsiella pneumoniae (17.3%); few anaerobes were isolated (Table 1). C/T + MTZ was non-inferior to MEM + pbo for clinical cure in the CE population (C/T + MTZ, 95.2%; MEM + pbo, 93.1%; difference, 2.1% [95% CI, −4.7% to 8.8%]). Results for key secondary endpoints were comparable between treatment groups (Table 2). Rates of AEs were generally similar between treatment groups (Table 3). Conclusion C/T + MTZ was non-inferior to MEM + pbo in the treatment of adult Chinese participants with cIAI and demonstrated a favorable safety profile. Disclosures Xiaofei Chen, n/a, MSD, China (Employee) Xiaoling Du, n/a, MSD, China (Employee) Ye Wang, n/a, MSD, China (Employee) Hui Wang, n/a, MSD, China (Employee) Fang Sun, n/a, MSD, China (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

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