Summary Background Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa ...compared with placebo or entacapone in patients with Parkinson's disease and motor fluctuations. Methods We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinson's disease with end-of-dose motor fluctuations. Patients aged 30–83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14–15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov , NCT01568073. Findings Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was −56·0 min (SE 13·4; 95% CI −82·3 to −29·7) for placebo, −96·3 min (13·4; −122·6 to −70·0) for entacapone, −91·3 min (13·5; −117·7 to −64·8) for opicapone 5 mg, −85·9 min (13·7; −112·8 to −59·1) for opicapone 25 mg, and −116·8 min (14·0; −144·2 to −89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline −60·8 min, 95% CI −97·2 to −24·4; p=0·0015) and non-inferior to entacapone (−26·2 min, −63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group. Interpretation The addition of opicapone 50 mg to levodopa treatment in patients with Parkinson's disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit. Funding BIAL.
Abstract
Background
Comorbidities and socioeconomic issues impact outcome of rotator cuff tear (RCT) repair. There are no data on RCT repair outcome from developing regions. We determined the impact ...of obesity and smoking following RCT repair in a low-income population.
Methods
This is a retrospective case series. Forty-seven shoulders of 42 patients subjected to open or arthroscopic repair of a RCT with a minimum of 2 years follow-up were cross-sectionally evaluated. Patients were seen in the Orthopaedic Service of the Hospital Geral de Fortaleza-CE, Brazil between March and September 2018. RCT were classified as partial or full-thickness lesions. Fatty infiltration (Goutallier) and tendon retraction (Patte) were recorded as well as obesity (BMI > 30), literacy >/≤ 8 school years (SY) and smoking status 6 months prior to surgery (present/absent). Outcomes included pain (visual analogue scale; VAS, 0–10 cm), range of motion active forward flexion and external rotation (ER), UCLA and ASES scoring.
Results
Patients were 59.9 ± 7.4 years-old, 35(74.4%) female with 19 (17.1–30.2 IQR) median of months from diagnosis to surgery and 25 median months of follow-up (26.9–34.0 IQR); over 90% declared < 900.00 US$ monthly family income and two-thirds had ≤8 SY. Forty patients (85.1%) had full-thickness tears, 7 (14.9%) had Goutallier ≥3 and over 80% had < Patte III stage. Outcomes were similar regardless of fatty infiltration or tendon retraction staging. There were 17 (36.1%) smokers and 13 (27.6%) obese patients. Outcome was similar when comparing obese vs non-obese patients. Smokers had more pain (
P
= 0.043) and less ER (
P
= 0.029) with a trend towards worse UCLA and ASES scores as compared to non-smokers though differences did not achieve minimal clinically important difference (MCID) proposed for surgical RCT treatment. After adjusting for obesity, VAS and ER values in smokers were no longer significant (
P
= 0.2474 and 0.4872, respectively).
Conclusions
Our data document outcomes following RCT repair in a low-income population. Smoking status but not obesity impacted RCT repair outcome though not reaching MCID for surgical treatment.
Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT ...inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects.
To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations.
This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014.
The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time.
A total of 427 patients (258 men 60.4% and 169 women 39.6%; mean SD age, 63.1 8.8 years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was -64.5 (14.4) minutes for the placebo group, -101.7 (14.9) minutes for the 25-mg/d opicapone group, and -118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, -54.3 95% CI, -96.2 to -12.4 minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, -37.2 95% CI, -80.8 to 6.4 minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (-126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase.
Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated.
clinicaltrials.gov Identifier: NCT01227655.
Reverse shoulder arthroplasty (RSA) is a valuable treatment for rotator cuff arthropathy (RCA) in developed regions. Socioeconomic issues impact access to specialized care and there is a lack of data ...on RSA outcomes in developing regions. We present our 24-month follow-up on RSA surgeries to treat RCA in our low-income population.
Prospective evaluation of 26 patients subjected to RSA at Hospital Geral de Fortaleza-CE, Brazil, between January 2018 and December 2020. Literacy >/≤ 8 school years(SY) and income were documented. Outcomes considered pain (visual analogue scale; VAS) as well as SSV, SPADI, ASES, and UCLA scoring, and range of motion forward flexion (FF); external rotation (ER).
Patients were 68.5 ± 7.6 years-old with 16(61.5%) females; 65% had hypertension and 7 (26.9%) had diabetes. Over 90% declared < 900.00 US$ monthly family earnings and 10 (38.4%) patients declared ≤8 SY with > 80% exerting blue-collar jobs. Pain showed a significant reduction from baseline (8 ± 2) to 24 months (2.1 ± 2.3; p < 0.001). UCLA (10.3 ± 5.6 and 28.6 ± 7.2), ASES (16.7 ± 10.8 and 63.1 ± 28.4), SSV (326 ± 311 and 760 ± 234), and SPADI (98.3 ± 26.5) scores significantly improved from baseline to 24 months, achieving minimal clinically important difference. FF (89.2° ± 51.2° to 140.6 ± 38.3°) and ER (19.2° ± 22.5 to 33.4° ± 20.6°) significantly improved from baseline to 24 months (p = 0.004 and 0.027, respectively). There were 5 non-serious adverse events with one surgical revision. All patients returned to daily life activities.
This is the first outcome report 2 years following RSA in a low-income population. Data indicate this procedure is justifiable regardless of socioeconomic issues.
This was a double-blind, randomised, placebo-controlled study to investigate the pharmacokinetics and safety of trans-resveratrol. In four groups of ten healthy adult subjects (five males and five ...females), two subjects were randomized to receive placebo and eight subjects to receive trans-resveratrol 25, 50, 100 or 150 mg, six times/day, for thirteen doses. Peak plasma concentrations of trans-resveratrol were reached at 0.8-1.5 h postdose. Following the 13th dose of trans-resveratrol 25, 50, 100 and 150 mg, mean peak plasma concentration (Cmax) was 3.89, 7.39, 23.1 and 63.8 ng/mL and mean area under the plasma concentration-time curve (AUC₀₋τ) was 3.1, 11.2, 33.0 and 78.9 ng·h/mL. Interindividual variability was high, with coefficients of variation >40%. Trans-resveratrol half-life was 1-3 h following single-doses and 2-5 h following repeated dosing. Trough (Cmin) concentrations were less, not equals1 ng/mL following 25 and 50 mg, 3 ng/mL following 100 mg and < 10 ng/mL following 150 mg. Trans-resveratrol pharmacokinetics showed circadian variation. Adverse events were mild in severity and similar between all groups. In conclusion, repeated administration was well-tolerated but produced relatively low plasma concentrations of trans-resveratrol, despite the high doses and short dosing interval used. Bioavailability was higher after morning administration.
This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BIA 10‐2474, a fatty acid amide hydrolase (FAAH) inhibitor, after first administration to healthy male and ...female participants. Participants (n = 116) were recruited into this phase I, double‐blind, randomized, placebo‐controlled, single ascending dose and multiple ascending dose (10‐day) study. The primary outcome was the safety and tolerability of BIA 10‐2474. Secondary outcomes were pharmacokinetics of BIA 10‐2474 and pharmacodynamics, considering plasma concentrations of anandamide and three other fatty acid amides (FAAs) and leukocyte FAAH activity. Single oral doses of 0.25–100 mg and repeated oral doses of 2.5–50 mg were evaluated. BIA 10‐2474 was well tolerated up to 100 mg as a single dose and up to 20 mg once daily for 10 days. In the cohort receiving repeated administrations of 50 mg, there were central nervous system adverse events in five of six participants, one with fatal outcome, which led to early termination of the study. BIA 10‐2474 showed a linear relationship between dose and area under plasma concentration‐time curve (AUC) across the entire dose range and reached steady state within 5–6 days of administration, with an accumulation ratio, based on AUC0–24h, of <2 on Day 10. BIA 10‐2474 was rapidly absorbed with a mean terminal elimination half‐life of 8–10 hours (Day 10). BIA 10‐2474 caused reversible, dose‐related increases in plasma FAAs. In conclusion, we propose that these data, as well as the additional data generated since the clinical trial was stopped, do not provide a complete mechanistic explanation for the tragic fatality.
Background
Cost‐effectiveness studies are highly dependent on the models, settings, and variables used and should be based on systematic reviews. We systematically reviewed cost‐effectiveness studies ...that address screening for gastric cancer and/or surveillance of precancerous conditions and lesions.
Materials and Methods
A systematic review of cost‐effectiveness studies was performed by conducting a sensitive search in seven databases (PubMed, Scopus, Web of Science, Current Contents Connect, Centre for Reviews and Dissemination, Academic Search Complete, and CINAHL Plus), independently evaluated by two investigators. Articles were evaluated for type of study, perspective, model, intervention, incremental cost‐effectiveness ratio, clinical or cost variables, and quality, according to published guidelines.
Results
From 2395 s, 23 articles were included: 19 concerning population screening and 4 on following up premalignant lesions. Studies on Helicobacter pylori screening concluded that serology was cost‐effective, depending on cancer incidence and endoscopy cost (incremental cost‐effectiveness ratio: 6264–25,881), and eradication after endoscopic resection was also cost‐effective (dominant) based on one study. Studies on imaging screening concluded that endoscopy was more cost‐effective than no screening (incremental cost‐effectiveness ratio: 3376–26,836). Articles on follow‐up of premalignant lesions reported conflicting results (incremental cost‐effectiveness ratio: 1868–72,519 for intestinal metaplasia; 18,600–39,800 for dysplasia). Quality assessment revealed a unanimous lack of a detailed systematic review and fulfillment of a median number of 23 items (20–26) of 35 possible ones.
Conclusions
The available evidence shows that Helicobacter pylori serology or endoscopic population screening is cost‐effective, while endoscopic surveillance of premalignant gastric lesions presents conflicting results. Better implementation of published guidelines and accomplishment of systematic detailed reviews are needed.
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