Safety and efficacy of fostamatinib in rheumatoid arthritis patients with an inadequate response to methotrexate in phase II OSKIRA-ASIA-1 and OSKIRA-ASIA-1X study

Rheumatology ◽  
2020 ◽  
Author(s):  
Yoshiya Tanaka ◽  
David Millson ◽  
Shigeru Iwata ◽  
Shingo Nakayamada
Keyword(s):  
Adverse Events ◽  
Physical Function ◽  
Phase Ii ◽  
Signs And Symptoms ◽  
Trial Registration ◽  
Inadequate Response ◽  
Double Blind ◽  
Phase Ii Studies ◽  
Group A

Abstract Objective The primary objectives of two phase II studies of fostamatinib were to evaluate efficacy (OSKIRA-Asia-1: NCT01569074) and long-term safety/tolerability (OSKIRA-Asia-1X: NCT01640054) in patients from Asia with active RA despite MTX treatment. Methods OSKIRA-Asia-1 was a 12-week, multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive one of four fostamatinib doses (groups A–D; n = 31, 33, 33, 33) or placebo (group E; n = 33). OSKIRA-Asia-1X was a long-term extension study (100 mg fostamatinib qd) of patients who completed OSKIRA-Asia-1. RA signs and symptoms were measured by ACR response criteria and DAS based on a 28-joint count. Physical function status was assessed with the HAQ–Disability Index. Safety findings were monitored. Results In OSKIRA-Asia-1, fostamatinib revealed numerical improvements in ACR 20% response (ACR20) at week 12 in group A (100 mg bid) and group B (100 mg bid, then 150 mg qd) vs placebo. Statistically significant improvements in ACR20 and ACR50 at week 8 and in ACR70 at week 12, and statistically significant achievement in low disease activity (defined as DAS based on a 28-joint count ≤3.2 based on C-reactive protein) occurred in groups A and B. Improvement in physical function was numerically higher in group A. The most common adverse events were hypertension, diarrhoea and neutropenia. In OSKIRA-Asia-1X, the most common adverse events were nasopharyngitis, hypertension, RA and neutropenia. Conclusion Fostamatinib achieved both statistically and clinically significant improvements in RA signs and symptoms. The safety and tolerability of fostamatinib (plus MTX) were consistent with previous studies. Trial registration OSKIRA-Asia-1 trial registration: https://clinicaltrials.gov, NCT01569074; OSKIRA-Asia-1X trial registration: https://clinicaltrials.gov, NCT01640054.

scholarly journals Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial

2021 ◽  
pp. annrheumdis-2020-219214
Author(s):  
Bernard Combe ◽  
Alan Kivitz ◽  
Yoshiya Tanaka ◽  
Désirée van der Heijde ◽  
J Abraham Simon ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Events ◽  
Physical Function ◽  
Structural Damage ◽  
Signs And Symptoms ◽  
Randomised Clinical Trial ◽  
Janus Kinase ◽  
Phase Iii ◽  
Inadequate Response ◽  
Double Blind

ObjectiveTo evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).MethodsThis 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.ResultsThe proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.ConclusionsFilgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab.Trial registration numberNCT02889796.

Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy

2007 ◽  
Vol 67 (4) ◽  
pp. 547-554 ◽  
Author(s):  
M C Genovese ◽  
M Schiff ◽  
M Luggen ◽  
J-C Becker ◽  
R Aranda ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Events ◽  
Sleep Problems ◽  
Inadequate Response ◽  
C Reactive Protein ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Reactive Protein ◽  
Sf 36

Objective:To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis.Methods:Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept ∼10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years.Results:317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (⩽3.2) and DAS28 (C-reactive protein)-defined remission (<2.6) increased from 18.3% (13.0, 23.5) to 32.0% (24.6, 39.4) and 11.1% (6.8, 15.3) to 20.3% (13.9, 26.6). Clinically meaningful improvements in SF-36, pain, fatigue and sleep problems were also maintained throughout the 2 years of abatacept treatment.Conclusion:No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease.Trial registration number:NCT00124982.

Atopische Dermatitis: IL-13-Antikörper macht Hoffnung auf gut verträgliche und lang wirkende Therapieoption

2021 ◽  
pp. 1-2
Author(s):  
Sandra Philipp
Keyword(s):  
Atopic Dermatitis ◽  
Initial Period ◽  
Human Monoclonal Antibody ◽  
Life Quality ◽  
Signs And Symptoms ◽  
Phase Iii ◽  
Inadequate Response ◽  
Double Blind ◽  
Topical Corticosteroids ◽  
Phase Ii Studies

<b>Background:</b> Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. <b>Objectives:</b> To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. <b>Methods:</b> In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator’s Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. <b>Results:</b> At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1–13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8–16·4; P &#x3c; 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5–17·7; P &#x3c; 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8–27·3; P &#x3c; 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16-week initial period. <b>Conclusions:</b> Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.

Tocilizumab Inhibits Structural Joint Damage and Improves Physical Function in Patients with Rheumatoid Arthritis and Inadequate Responses to Methotrexate: LITHE Study 2-year Results

2013 ◽  
Vol 40 (2) ◽  
pp. 113-126 ◽  
Author(s):  
ROY M. FLEISCHMANN ◽  
ANNE-MARIE HALLAND ◽  
MAREK BRZOSKO ◽  
RUBEN BURGOS-VARGAS ◽  
CHRISTOPHER MELA ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Physical Function ◽  
Safety Data ◽  
Joint Damage ◽  
Area Under The Curve ◽  
Signs And Symptoms ◽  
Inadequate Response ◽  
Open Label ◽  
Double Blind ◽  
Structural Joint

Objective.To assess radiographic progression, physical function, clinical disease activity, and safety in patients with rheumatoid arthritis (RA) who had inadequate response to methotrexate (MTX) and who were treated with tocilizumab-MTX or MTX during Year 2 of a 2-year study.Methods.During Year 1, patients were randomized to placebo-MTX, 4 mg/kg tocilizumab-MTX, or 8 mg/kg tocilizumab-MTX. During Year 2, patients continued the initial double-blind treatment or switched to open-label 8 mg/kg tocilizumab-MTX. Co-primary endpoints at Week 104 were mean change from baseline in Genant-modified Total Sharp Score (GmTSS) and adjusted mean area under the curve (AUC) for change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI). Signs and symptoms of RA and safety were also evaluated.Results.At Week 104, mean change from baseline in GmTSS was significantly lower for patients initially randomized to tocilizumab-MTX 4 mg/kg (0.58; p = 0.0025) or 8 mg/kg (0.37; p < 0.0001) than for patients initially randomized to placebo-MTX (1.96). Adjusted mean AUC of change from baseline in HAQ-DI was also significantly lower in patients initially randomized to tocilizumab-MTX 4 mg/kg (–287.5; p < 0.0001) or 8 mg/kg (–320.8; p < 0.0001) than in patients initially randomized to placebo-MTX (–139.4). Signs and symptoms of RA were maintained or showed improvement. No new safety signals were noted.Conclusion.Compared with placebo-MTX, tocilizumab-MTX significantly inhibited structural joint damage and improved physical function in patients with RA who previously had inadequate response to MTX. An extension of this study is continuing and will provide additional longterm efficacy and safety data. National Clinical Trials registry NCT00106535.

scholarly journals Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2

2020 ◽  
pp. annrheumdis-2020-218870
Author(s):  
Philip J Mease ◽  
Apinya Lertratanakul ◽  
Jaclyn K Anderson ◽  
Kim Papp ◽  
Filip Van den Bosch ◽  
...  
Keyword(s):  
Psoriatic Arthritis ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Signs And Symptoms ◽  
Janus Kinase ◽  
Inadequate Response ◽  
Double Blind ◽  
Clinical Trial Registration ◽  
American College Of Rheumatology ◽  
Trial Drug

BackgroundUpadacitinib is a Janus kinase inhibitor under evaluation for the treatment of psoriatic arthritis (PsA). We evaluated upadacitinib in patients with PsA and prior inadequate response or intolerance to at least one biologic disease-modifying antirheumatic drug (DMARD).MethodsIn this 24-week randomised, placebo-controlled, double-blind, phase 3 trial, 642 patients were randomised (2:2:1:1) to once per day upadacitinib 15 mg or 30 mg, placebo followed by upadacitinib 15 mg or placebo followed by upadacitinib 30 mg at week 24. The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 12. Achievement of minimal disease activity (MDA) was assessed at week 24. Treatment-emergent adverse events are reported for all patients who received at least one dose of trial drug.ResultsAt week 12, significantly more patients receiving upadacitinib 15 mg and 30 mg versus placebo achieved ACR20 (56.9% and 63.8% vs 24.1%; p<0.001 for both comparisons). At week 24, MDA was achieved by more upadacitinib 15 mg-treated (25.1%) and 30 mg-treated patients (28.9%) versus placebo (2.8%; p<0.001 for both comparisons). Generally, the rates of treatment-emergent adverse events were similar with placebo and upadacitinib 15 mg and higher with upadacitinib 30 mg at week 24. Rates of serious infections were 0.5%, 0.5% and 2.8% with placebo, upadacitinib 15 mg and upadacitinib 30 mg, respectively.ConclusionIn this trial of patients with active PsA who had inadequate response or intolerance to at least one biologic DMARD, upadacitinib 15 mg and 30 mg was more effective than placebo over 24 weeks in improving signs and symptoms of PsA.Clinical trial registration numberNCT03104374

scholarly journals Efficacy and safety of fremanezumab in patients with migraine and inadequate response to prior preventive treatment: subgroup analyses by country of a randomized, placebo-controlled trial

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Egilius L. H. Spierings ◽  
Mikko Kärppä ◽  
Xiaoping Ning ◽  
Joshua M. Cohen ◽  
Verena Ramirez Campos ◽  
...  
Keyword(s):  
United States ◽  
Czech Republic ◽  
Adverse Events ◽  
Least Squares ◽  
The United States ◽  
Inadequate Response ◽  
Double Blind ◽  
Monthly Average ◽  
Preventive Medication ◽  
Subgroup Analyses

Abstract Background The FOCUS study evaluated the efficacy of migraine preventive medications across different countries within the same patient population, particularly for patients with difficult-to-treat migraine. These prespecified subgroup analyses evaluated efficacy by country in the FOCUS study of fremanezumab in adults with episodic migraine or chronic migraine and documented inadequate response to 2 to 4 migraine preventive medication classes. Methods Overall, 838 participants were enrolled in the FOCUS study, a randomized, double-blind, placebo-controlled, parallel-group, phase 3b study performed at 104 sites. For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched placebo. The primary efficacy endpoint was the mean change from baseline in monthly average migraine days over 12 weeks of double-blind treatment, evaluated by country in these subgroup analyses. Results Of 14 countries contributing data, the Czech Republic (n = 188/838; 22%), the United States (n = 120/838; 14%), and Finland (n = 85/838; 10%) enrolled the most patients. Changes from baseline in monthly average migraine days over 12 weeks were significantly greater with fremanezumab versus placebo for patients in these countries: Czech Republic (least-squares mean difference versus placebo [95% confidence interval]: quarterly fremanezumab, − 1.9 [− 3.25, − 0.47]; P = 0.009; monthly fremanezumab, − 3.0 [− 4.39, − 1.59]; P < 0.001), the United States (quarterly fremanezumab, − 3.7 [− 5.77, − 1.58]; P < 0.001; monthly fremanezumab, − 4.2 [− 6.23, − 2.13]; P < 0.001), and Finland (quarterly fremanezumab, − 3.0 [− 5.32, − 0.63]; P = 0.014; monthly fremanezumab, − 3.9 [− 6.27, − 1.44]; P = 0.002). Results were comparable for the remaining 9 countries, with the least-squares mean difference versus placebo ranging from – 5.6 to – 2.4 with quarterly fremanezumab and from − 5.3 to − 1.5 with monthly fremanezumab. Incidences of serious adverse events and adverse events leading to discontinuation were low and comparable across countries and treatment groups. Conclusions Monthly and quarterly fremanezumab significantly reduced the monthly average number of migraine days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2 to 4 migraine preventive medication classes. Trial registration ClinicalTrials.gov Identifier: NCT03308968.

MO126CLINICAL AND BIOMARKER CHARACTERISTICS OF PATIENTS WITH C3G OR IC-MPGN ENROLLED IN TWO PHASE II STUDIES INVESTIGATING THE FACTOR D INHIBITOR DANICOPAN*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Carla Nester ◽  
Steven Podos ◽  
Jonathan Hogan ◽  
Gerald Appel ◽  
Andrew Bomback ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kidney Diseases ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Complement Factor ◽  
Open Label ◽  
Double Blind ◽  
Phase Ii Studies ◽  
Complement Dysregulation ◽  
Extension Trial

Abstract Background and Aims C3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare, progressive kidney diseases requiring a biopsy for definite diagnosis. Both C3G and IC-MPGN are attributed to complement dysregulation, with dysregulation of the alternative pathway established in C3G and implicated in IC-MPGN (alongside classical pathway activation by immune complexes). We describe the baseline biomarker and clinical characteristics of patients participating in two C3G/IC-MPGN phase II studies of the investigational, oral complement factor D (FD) inhibitor, danicopan (ALXN2040/ACH-4471). Method The first study (NCT03369236) was a double-blind, placebo-controlled, randomised, 6-month (+open label extension) trial of patients with biopsy-confirmed C3G of the native kidney treated with danicopan or placebo. The second study (NCT03459443) was a single-arm, open-label, 12-month (+extension) trial of patients with biopsy-confirmed C3G or IC-MPGN treated with danicopan. In both studies, all patients were to have proteinuria ≥500 mg/day and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease equation for patients ≥18 years and the Schwartz equation for patients &lt;18 years). Complement biomarkers including, but not limited to, C3, C4, AP activity, classical pathway activity, FD, Ba, Bb, sC5b-9, and C5 were measured in serum or plasma prior to dosing. Spearman correlation coefficients (rs) were determined between biomarkers of complement, eGFR, and/or proteinuria. Results A total of 35 patients were included in this analysis (13 from study 1 and 22 from study 2). The majority of patients were male (9 [69%] in study 1, 12 [55%] in study 2), with mean (SD) ages at baseline of 25.2 (7.63) years in study 1 and 24.3 (9.90) years in study 2. Most patients had received prior angiotensin converting enzyme inhibitors/receptor blockers (12 [92%] in study 1, 19 [86%] in study 2), and/or immunosuppressants (10 [77%] in study 1, 12 [55%] in study 2). Baseline clinical and biomarker data are shown in Table 1. Baseline eGFR was moderately correlated with proteinuria (uPCR24, rs=-0.40 [p=0.022]); baseline uPCR24 was also moderately correlated with Ba (rs=0.42 [p=0.016]) and FD (rs=0.53 [p=0.002]). Ba and FD elevations showed strong correlations with lower eGFR (rs=-0.79 and -0.88, respectively [p&lt;0.0001]), as seen in Figure 1A and B. Reduced circulating C3 strongly correlated with increased sC5b-9 (rs=-0.70 [p&lt;0.0001]) and reduced C5 level (rs=0.80 [p&lt;0.0001]), as seen in Figure 1C and D. Conclusion Data from two danicopan clinical studies in C3G patients show correlations with renal impairment and proteinuria were observed for some, but not all, complement biomarkers. Factor Ba and FD are strongly associated with eGFR, suggesting that these biomarkers cannot easily be used as markers of complement dysregulation or activity. Interpretation of changes in these complement proteins needs to include not only the nature of the complement dysregulation and influence of the complement therapeutic being tested, but also eGFR. Additional urinary biomarkers, biopsy findings, autoantibodies, and genetic variants are currently being analysed and findings from this study will contribute to a better understanding of C3G and IC-MPGN.

scholarly journals Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
S. Dian ◽  
V. Yunivita ◽  
A. R. Ganiem ◽  
T. Pramaesya ◽  
L. Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Standard Dose ◽  
Geometric Mean ◽  
Phase Iii ◽  
High Dose ◽  
Treatment Area ◽  
Double Blind ◽  
Time Curve

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)

scholarly journals Safety and effectiveness of lurasidone in adolescents with schizophrenia: results of a 2-year, open-label extension study

CNS Spectrums ◽  
2020 ◽  
pp. 1-11
Author(s):  
Christoph U. Correll ◽  
Robert L. Findling ◽  
Michael Tocco ◽  
Andrei Pikalov ◽  
Ling Deng ◽  
...  
Keyword(s):  
Body Weight ◽  
Adverse Events ◽  
Rating Scales ◽  
Extension Study ◽  
Open Label ◽  
Double Blind ◽  
Syndrome Scale ◽  
Open Label Extension ◽  
Glycemic Indices

Abstract Background Minimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia. Methods Patients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score. Results About 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of −15.6 at week 52 and −18.4 at week 104. Conclusion In adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

scholarly journals Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study)

2016 ◽  
Vol 76 (5) ◽  
pp. 811-820 ◽  
Author(s):  
Thomas Bardin ◽  
Robert T Keenan ◽  
Puja P Khanna ◽  
Jeff Kopicko ◽  
Maple Fung ◽  
...  
Keyword(s):  
Adverse Events ◽  
Laboratory Data ◽  
Standard Of Care ◽  
Phase Iii ◽  
Controlled Study ◽  
Inadequate Response ◽  
Double Blind ◽  
Significant Treatment ◽  
End Points ◽  
Registration Number

ObjectivesDetermine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial.MethodsPatients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data.ResultsPatients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively.ConclusionLesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.Trial registration numberNCT01493531.

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