Efficacy, pharmacokinetics and safety of subcutaneous versus intravenous CT-P13 in rheumatoid arthritis: a randomized phase I/III trial.

OBJECTIVE: To assess non-inferiority of s.c. to i.v. CT-P13 in RA. METHODS: Patients with active RA and inadequate response to MTX participated in this phase I/III double-blind study at 76 sites. Patients received CT-P13 i.v. 3 mg/kg [week (W) 0 and W2] before randomization (1:1) at W6 to CT-P13 s.c. via pre-filled syringe (PFS) 120 mg biweekly until W28, or CT-P13 i.v. 3 mg/kg every 8 weeks until W22. Randomization was stratified by country, W2 serum CRP and W6 body weight. From W30, all patients received CT-P13 s.c. In a usability sub-study, patients received CT-P13 s.c. via auto-injector (W46-54) then PFS (W56-64). The primary endpoint was change (decrease) from baseline in disease activity score in 28 joints (DAS28)-CRP at W22 (non-inferiority margin: -0.6). RESULTS: Of 357 patients enrolled, 343 were randomized to CT-P13 s.c. (n = 167) or CT-P13 i.v. (n = 176) at W6. The least-squares mean change (decrease) from baseline (standard error) in DAS28-CRP at W22 was 2.21 (0.22) for CT-P13 s.c. (n = 162) and 1.94 (0.21) for CT-P13 i.v. [n = 168; difference 0.27 (95% CI: 0.02, 0.52)], establishing non-inferiority. Efficacy findings were similar between arms at W54. Safety was similar between arms throughout: 92 (54.8%; CT-P13 s.c.) and 117 (66.9%; CT-P13 i.v.) patients experienced treatment-emergent adverse events (from W6). There were no treatment-related deaths or new safety findings. Usability was similar for CT-P13 s.c. via auto-injector or PFS. CONCLUSION: CT-P13 s.c. was non-inferior to CT-P13 i.v. in active RA. The convenience of s.c. administration could benefit patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03147248.

Comparative clinical efficacy and safety of the proposed biosimilar ABP 710 with infliximab reference product in patients with rheumatoid arthritis.

BACKGROUND: ABP 710 is being developed as a biosimilar to infliximab reference product (RP). Analytical similarity and pharmacokinetic equivalence between the two have been previously demonstrated. Here we report results from a comparative clinical study that evaluated the efficacy and safety of ABP 710 relative to the RP in patients with rheumatoid arthritis (RA). METHODS: In this multicenter, randomized, double-blind, 50-week equivalence study, patients with moderate to severe active RA despite methotrexate received 3-mg/kg infusions of ABP 710 or RP at predetermined intervals based on initial randomization and then with re-randomization at week 22. The primary endpoint was response difference (RD) of ACR20 at week 22, with clinical equivalence evaluated based on 90% CI of - 15%, 15%. Secondary endpoints included Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP), ACR20, ACR50, and ACR70 across time, as well as safety and immunogenicity assessments. RESULTS: A total of 558 patients were randomized for the initial treatment (ABP 710 n = 279; RP n = 279). The estimated RD of ACR20 at week 22 was 9.37% with 90% CI (2.67%, 15.96%). The lower bound was within the pre-specified criteria, thus confirming non-inferiority; the upper bound exceeded the pre-specified criteria by 0.96% such that superiority could not be ruled out statistically. In a post hoc analysis with adjustment for random imbalance in baseline factors, the CI of RD was narrowed (0.75%, 13.62%). Changes from baseline in DAS28-CRP as well as ACR20, ACR50, and ACR70 response rates across time and hybrid ACR evaluations were similar for the initial and initial/re-randomized treatment groups. Adverse events and incidence of anti-drug antibodies were similar between treatment groups. CONCLUSIONS: These efficacy and safety results support similarity with no clinically meaningful differences between ABP 710 and infliximab RP. Although we were unable to statistically confirm non-superiority, post hoc analysis was supportive of non-superiority. DAS28-CRP, ACR20, ACR50, ACR70, and hybrid ACR evaluations over the entire study were consistently comparable as were safety and immunogenicity. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT02937701. Registered August 30, 2016.

High-Frequency Repetitive Transcranial Magnetic Stimulation Can Improve Depression in Parkinson's Disease: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: A recent evidence-based guideline demonstrated that bilateral repetitive transcranial magnetic stimulation (rTMS) over the motor cortex (M1) can improve motor symptoms of Parkinson's disease (PD). We conducted a randomized, double-blind, placebo-controlled study to evaluate the impact of bilateral M1 rTMS on depression in PD. METHODS: Forty-six patients with PD and mild-to-moderate depression were randomly assigned to active (n = 23) and sham (n = 23) rTMS. Two patients in the sham group did not complete the protocol because of reasons unrelated to the study. High-frequency rTMS was applied over the primary motor cortex bilaterally for 10 days. An investigator blinded to the treatment performed three video-taped examinations on each patient: before stimulation (baseline), and 1 day (short-term effect) and 30 days after the treatment session ended (long-term effect). The primary end point was the changes in depression, while secondary end points included health-related quality of life scales and Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: In the actively treated group, not only did the severity of depression improve (from 17 to 7 points, Montgomery-Åsberg Depression Rating Scale, median values, p < 0.001), but also the health-related quality of life (from 25.4 to 16.9 points, PDQ-39 summary index, median values, p < 0.001). Besides, we could also demonstrate an improvement in MDS-UPDRS Motor Examination (from 26 to 20 points, median values, p < 0.05). In the sham-treated group, none of the examined tests and scales improved significantly after treatment. CONCLUSIONS: Our results demonstrate the beneficial effects of high-frequency bilateral M1 rTMS on depression and health-related quality of life in PD. However, this effect of rTMS should also be confirmed in patients with severe depression by further clinical trials.

Minimal clinically important difference on the Motor Examination part of MDS-UPDRS.

BACKGROUND: Recent studies increasingly utilize the Movement Disorders Society Sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS). However, the minimal clinically important difference (MCID) has not been fully established for MDS-UPDRS yet. OBJECTIVE: To assess the MCID thresholds for MDS-UPDRS Motor Examination (Part III). METHODS: 728 paired investigations of 260 patients were included. At each visit both MDS-UPDRS and Clinician-reported Global Impression-Improvement (CGI-I) scales were assessed. MDS-UPDRS Motor Examination (ME) score changes associated with CGI-I score 4 (no change) were compared with MDS-UPDRS ME score changes associated with CGI-I score 3 (minimal improvement) and CGI-I score 5 (minimal worsening). Both anchor- and distribution-based techniques were utilized to determine the magnitude of MCID. RESULTS: The MCID estimates for MDS-UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening. CONCLUSIONS: MCID is the smallest change of scores that are clinically meaningful to patients. These MCID estimates may allow the judgement of a numeric change in MDS-UPDRS ME on its clinical importance.

[VALIDATION OF THE HUNGARIAN UNIFIED DYSKINESIA RATING SCALE]. / AZ EGYSÉGESÍTETT DYSKINESIA-PONTOZÓSKÁLA MAGYAR NYELVI VALIDÁCIÓJA.

BACKGROUND: The Unified Dyskinesia Rating Scale (UDysRS) was published in 2008. It was designed to be simultaneous valid, reliable and sensitive to therapeutic changes. The Movement Disorder Society organizing team developed guidelines for the development of official non-English translations consisting of four steps: translation/back-translation, cognitive pretesting, large field testing, and clinimetric analysis. The aim of this paper was to introduce the new UDysRS and its validation process into Hungarian. METHODS: After the translation of UDysRS into Hungarian and back-translated into English, it was reviewed by the UDysRS translation administration team. Subsequent cognitive pretesting was conducted with ten patients. For the large field testing phase, the Hungarian official working draft version of UDysRS was tested with 256 patients with Parkinson's disease having dyskinesia. Confirmatory factor analyses (CFA) determined whether the factor structure for the valid Spanish UDysRS could be confirmed in data collected using the Hungarian Official Draft Version. To become an official translation, the Comparative Fit Index (CFI) had to be ≥ 0.90 compared to the Spanish-language version. RESULTS: For the Hungarian UDysRS the CFI was 0.98. CONCLUSION: The overall factor structure of the Hungarian version was consistent with that of the Spanish version based on the high CFIs for the UDysRS in the CFA; therefore, this version was designated as the Official Hungarian Version Of The UDysRS.

Comparison of the efficacy of unipolar and bipolar electrode configuration during subthalamic deep brain stimulation.

Deep brain stimulation of the subthalamic nuclei (STN) is a well established treatment in advanced Parkinson's disease (PD). Based on the clinical efficacy and elicited side-effects, both unipolar and bipolar stimulation modes may be applied. Bipolar stimulation usually produces a more focused and therefore thinner area of tissue activated during stimulation than unipolar stimulation does. The primary aim of our clinical study was to quantify the different clinical efficacy between these two stimulation modes. Twenty-one patients with PD previously underwent bilateral STN DBS implantation were involved in the study. Approximately three years after the implantation, we evaluated rigidity, tremor and bradykinesia according to the Unified Parkinson's disease Rating Scale in a practically off condition. Keeping the cathode of the chronic stimulation setting constant, the amplitude of stimulation was changed between 0 and 3.6 V by 0.2 V steps. Subsequently, the improvements in rigidity, tremor and bradykinesia were compared between unipolar and bipolar modes using 60 µs pulse-width and 130 Hz frequency. Within the examined amplitude range, unipolar stimulation usually had a significantly higher efficacy than bipolar stimulation; however, also with a higher rate of side-effects (19% vs. 0%). Depending on the evaluated parkinsonian symptoms, the efficacy of uni- and bipolar stimulation was different. To achieve the same level of improvement during bipolar stimulation, approximately 0.4-0.5 V higher amplitude was required than in unipolar mode. However in some cases, the efficacy of bipolar stimulation was unable the reach that of unipolar stimulation within the examined amplitude range.

[Analysis of antiparkinsonian drug reduction after bilateral subthalamic deep brain stimulation]. / A kétoldali subthalamicus stimuláció hatékonysága az antiparkinson gyógyszereles változtatásának tükrében.

BACKGROUND: Bilateral deep brain stimulation of the subthalamic nuclei (STN) is a well-established and cost-effective treatment in advanced PD. OBJECTIVES: To quantitatively analyze the change in use of antiparkinsonian drugs one year after subthalamic deep brain stimulator (DBS) implantation in patients with idiopathic Parkinson's disease (PD). PATIENTS AND METHODS: Eighteen consecutive patients with advanced PD underwent bilateral STN DBS implantation were involved in the study. The stimulation achieved a stable and clear clinical benefit in all of the cases. One year after the implantation, drug usage of patients was analyzed and correlated with the postoperative symptomatic improvement measured by the modified Hoehn-Yahr, Schwab and England, and Unified Parkinson's Disease Rating Scales. Because none of the investigated variables followed the normal distribution, non-parametric Wilcoxon signed-rank, McNemar and Kendell's T tests were applied. RESULTS: Preoperatively, the patients used 12.05 +/- 4.57 tablets a day out of 3.19 +/- 0.97 different antiparkinsonian drugs, which was significantly reduced by deep brain stimulation to the application of 7.00 +/- 2.96 tablets out of 1-3 (1.84 +/- 0.76) drugs (p < 0.001). Meanwhile, the usage of amantadine, MAO-B and COMT inhibitors was also significantly decreased (p < 0.05). The dosage of dopaminerg medication was significantly lowered from 1136 mg to 706 mg expressed in levodopa equivalent dosage (p < 0.001) whereas the UPDRS-III also improved by 48.6%. CONCLUSION: Our study is in accordance with previously published international findings that antiparkinsonian medication can be significantly lowered after bilateral STN DBS. Because not only the dosage, but also the applied number of tablets were decreased, it may have resulted in a better compliance and quality of life.

The impact of left prefrontal repetitive transcranial magnetic stimulation on depression in Parkinson's disease: a randomized, double-blind, placebo-controlled study.

Based on several open-label and case studies, repetitive transcranial magnetic stimulation (rTMS) seems to have an antidepressive effect on patients with Parkinson's disease (PD). However, this hypothesis requires further confirmation. We conducted a randomized, double-blind placebo-controlled study to evaluate the effect of rTMS over the left dorsolateral prefrontal cortex (DLPFC) on depression and various motor and nonmotor features of PD. Twenty-two PD patients with mild or moderate depressive episodes were assigned into two groups, one receiving real-rTMS (90% of resting motor threshold, 5 Hz, 600 pulses-a-day for 10 days) over the left DLPFC, and another group receiving sham-rTMS. An investigator blinded to the treatment performed three video-taped examinations on each patient: before stimulation (baseline), 1 day (short term), and 30 days after treatment session ended (long-term effect). Mini-Mental State Examination, Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn-Yahr, Epworth Sleepiness, Visual Analog and Montgomery-Asberg Depression Rating Scales (MADRS), Beck Depression Inventory (BDI), and Trail making and Stroop tests were applied. In the actively treated group, not only depression rating scales showed significant improvement 30 days after treatment ended (BDI by 44.4% and MADRS by 26.1%), but also the accuracy of Stroop test (by 16%). We could also demonstrate an insignificant improvement in UPDRS-III by 7.5 points (31.9%, P = 0.06). In the sham-treated group none of the examined tests and scales improved significantly after sham stimulation. Our study demonstrated the beneficial effect of the left DLPFC rTMS on depression in PD lasting at least 30 days after treatment. However, this result should be confirmed in patients with severe depression by further clinical trials.

Influence of coronary artery stenosis severity and coronary collateralization on extent of chronic myocardial scar: insights from quantitative coronary angiography and delayed-enhancement MRI.

OBJECTIVES: In patients with chronic ischemic heart disease, the relationship between coronary artery lesion severity and myocardial scarring is unknown.The purpose of this study was to examine the relationship between proximal coronary artery stenosis severity, the amount of coronary collateralization, and myocardial scar extent in the distal distribution of the affected coronary artery based on both quantitative coronary angiography (QCA) and delayed-enhancement magnetic resonance imaging (DE-MRI). METHODS: Thirty-four patients (26 males, 8 females; age range: 35-86 years) with a coronary artery containing a single, proximal stenosis >/=30% by quantitative coronary angiography (QCA) underwent DE-MRI. The relationship between stenosis severity, collateralization, and myocardial scar morphology (area, transmurality and patchiness) was examined using linear mixed-model ANCOVA. RESULTS: There was a statistically significant correlation between stenosis severity and scar extent (r=0.53, p<0.01). Patients with hemodynamically significant stenoses (>/=70%) exhibited significantly greater collateralization (p<0.05) and scar extent (p<0.01) than patients with <70% stenosis. However, scarring was often found in patients with stenoses <70%. Also, greater stenosis severity (93+/-14%) and mean scar extent (41+/-35%) were found in patients with collaterals than in patients without collaterals (diameter stenosis 48+/-10%, p<0.01) (scar extent 19+/-29%, p=0.01). CONCLUSIONS: Using QCA and DE-MRI, we demonstrate a significant relationship between coronary artery stenosis severity and myocardial scar extent, in the absence of a documented history of acute infarction. The relationship likely reflects increasing ischemia leading to scar formation in the range of angiographically significant stenosis. However, in the absence of collateralization, scar was observed without significant stenosis, especially in females.