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ObjectiveTo explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG).MethodsIn this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1–29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29–43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44–99). Primary endpoint: change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints: change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores; safety.ResultsForty-three patients were randomized (rozanolixizumab: 21 patients; placebo: 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo: QMG (LS mean: −1.8 vs −1.2; difference: −0.7; 95% UCL: 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean: −1.8 vs −0.4; difference: −1.4; 95% UCL: −0.4), and MGC (LS mean: −3.1 vs −1.2; difference: −1.8; 95% UCL: 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab: 57%; placebo: 14%).ConclusionWhile change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422).Classification of evidenceThis study provides class I evidence that for patients with gMG, rozanolixizumab is well tolerated, but did not significantly improve QMG score.

Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.

Background Feedback from wearable biosensors may help assess motor function in Parkinson's disease (PD) patients and titrate medication. Kinesia 360 continuously monitors motor symptoms via wrist and ankle sensors. Methods PD0049 was a 12-week pilot study to investigate whether using Kinesia 360 at home could improve motor symptom management in PD patients starting transdermal dopamine agonist rotigotine. Adults with PD and insufficiently controlled motor symptoms (prescribed rotigotine) were randomized 1:1 to Control Group (CG) or Experimental Group (EG) before starting rotigotine. Motor symptoms were assessed in all patients at baseline and Week 12 (W12) using Unified PD Rating Scale (UPDRS) III and Kinesia ONE, which measures standardized motor tasks via a sensor on the index finger. Between baseline and W12, EG used Kinesia 360 at home; clinicians used the data to supplement standard care in adjusting rotigotine dosage. Results At W12, least squares mean improvements in UPDRS II (−2.1 vs 0.5, p = 0.004) and UPDRS III (−5.3 vs −1.0, p = 0.134) were clinically meaningfully greater, and mean rotigotine dosage higher (4.8 vs 3.9 mg/24 h) in EG (n = 19) vs CG (n = 20). Mean rotigotine dosage increase (+2.8 vs + 1.9 mg/24 h) and mean number of dosage changes (2.8 vs 1.8) during the study were higher in EG vs CG. Tolerability and retention rates were similar. Conclusion Continuous, objective, motor symptom monitoring using a wearable biosensor as an adjunct to standard care may enhance clinical decision-making, and may improve outcomes in PD patients starting rotigotine.

Introduction Rozanolixizumab targets the human neonatal Fc receptor (FcRn). By blocking IgG recycling, this first-in-class subcutaneously (SC) infused monoclonal antibody aims to improve the course of immunoglobulin G (IgG)-mediated autoimmune diseases by reducing pathogenic autoantibody levels. We report the completed Phase II, open-label study of rozanolixizumab in patients (pts) with primary immune thrombocytopenia (ITP; NCT02718716). Methods Eligibility: ≥18 yrs old; primary ITP ≥3 months (persistent/chronic); platelet count Results Of the 66 pts enrolled, 65 (98.5%) completed the study (one discontinued due to lack of efficacy, 4 mg/kg multiple-dose cohort). All pts were included in the safety set (SS) and full analysis set (FAS) while 64 were included in the per protocol set (PPS) and pharmacodynamic set (PD)-PPS. Two pts were excluded due to protocol deviations: procedural non-compliance and/or prohibited medication use. Overall, 51/66 (77.3%) pts reported ≥1 AE, mostly mild-to-moderate headaches (26/66 [39.4%]; Table 1). None of 4 serious AEs was treatment-related: genital tract bleeding (4 mg/kg group), thrombocytopenia (10 mg/kg), thrombocytopenia and platelet count decrease (both 15 mg/kg). One pt in each multiple-dose group and 7/12 and 9/12 pts (15 and 20 mg/kg, respectively), reported AEs (mostly headaches) deemed treatment-related (Table 1). No serious infections were seen. Baseline disease characteristics suggested a difficult to treat population, with a median of 5.8 years ITP duration, 4 prior ITP therapies and approx. 30% of pts having previously received thrombopoetin receptor agonists (Table 2). More pts receiving a single (15 and 20 mg/kg) rozanolixizumab SC infusion achieved platelet count ≥50x109/L (8/12 [66.7%] and 6/11 [54.5%; one pt excluded] in the 15 and 20 mg/kg groups, respectively) compared with those receiving multiple SC infusions: 5/14 (35.7%), 5/14 (35.7%; one pt excluded) and 5/11 (45.5%) in the 4, 7 and 10 mg/kg groups, respectively. In particular, median time to platelet count ≥50x109/L was considerably shorter in pts receiving a single dose of rozanolixizumab (7 and 5 days in the 15 and 20 mg/kg groups, respectively) compared with multiple SC infusions (14, 14 and 8 days in the 4, 7 and 10 mg/kg groups, respectively). For early responses by Day 8, a platelet count of ≥50x109/L was achieved by 7/12 (58.3%) and 6/11 (54.5%) pts in the 15 and 20 mg/kg dose groups, respectively (13/23 pts receiving a single infusion), compared with 1/14 (7.1%), 2/14 (14.3%) and 3/11 (27.3%) pts in the 4, 7 and 10 mg/kg groups, respectively (6/39 pts receiving multiple infusions). Dose-dependent increases in platelet count were observed with peak median counts >100x109/L in the 15 and 20 mg/kg groups (Table 3). Dose-dependent decreases in mean serum IgG concentrations were observed by Day 8 (Table 3). The 20 mg/kg single-dose group achieved their nadir on Day 8 (mean IgG concentration: 3.9 g/L, reduction of 5.9 g/L (60.0%) from baseline), while the 5 x 4 mg/kg group achieved their nadir on Day 29 (mean IgG concentration: 5.6 g/L, reduction of 4.0 g/L (43.6%) from baseline). Exploratory analyses, using data at baseline and Day 8, suggested that the magnitude of serum IgG decrease was associated with the corresponding platelet increase. Conclusion Rozanolixizumab was well tolerated across all dose groups (4-20 mg/kg) with mild-to-moderate headaches seen at higher doses; no patient discontinued the study due to side effects. While improvements in platelet count and decreases in IgG levels were seen at all doses of rozanolixizumab, the single SC infusions (15 and 20 mg/kg) achieved these efficacy endpoints both sooner (by Day 8), more frequently and at numerically greater levels than multiple doses. These safety, tolerability, and efficacy data support Phase III development of rozanolixizumab in patients with primary ITP. Disclosures Robak: Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. Jarque:Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; CellTrion: Consultancy; Gilead: Consultancy, Speakers Bureau; Grifols: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Musteata:Arensia EM: Other: Principal Investigator; Institute of Oncology: Employment. Cooper:Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kiessling:UCB Biosciences: Employment, Equity Ownership. Massow:UCB Biosciences GmbH: Employment. Woltering:UCB: Employment. Snipes:UCB Biosciences Inc: Employment. Ke:UCB Pharma: Employment, Equity Ownership. Langdon:AstraZeneca: Consultancy; Conatus: Consultancy; Pfizer: Consultancy; UCB Pharma: Consultancy; Ziarco: Consultancy; MMV: Consultancy; Sigmoid Pharma: Consultancy; Mylan: Consultancy; Creablis: Consultancy. Haier:UCB Pharma Sprl: Employment, Equity Ownership. Bussel:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; 3S Bio: Speakers Bureau; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jolles:UCB Pharma: Consultancy, Other: Drug Safety Committee; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Shire/Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharming: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Investigate impact of 6-month earlier versus postponed initiation of rotigotine in patients with early Parkinson's disease (PD) with mild symptom severity.Long-term benefit of rotigotine in early-PD has been demonstrated: SP702 (NCT00594165) and SP716 (NCT00599196) were long-term, open-label extensions of double-blind, placebo-controlled studies of 6-month maintenance; rotigotine was well tolerated for up to 6 years, and demonstrated efficacy (Unified Parkinson's Disease Rating Scale [UPDRS] II + III below baseline) for ∼ 2 years (SP702) and ∼ 4 years (SP716).Post hoc analysis of patients at Hoehn and Yahr 1-2; groups defined by treatment received in 6-month double-blind studies: 'Rotigotine-Rotigotine' received rotigotine (n = 221), 'Placebo-Rotigotine' received placebo (n = 125).At the start of open-label rotigotine maintenance, UPDRS II + III mean ± SD change from double-blind baseline was: -8.5 ± 10.6 'Rotigotine-Rotigotine', -7.7 ± 9.0 'Placebo-Rotigotine.' After this initial improvement scores gradually increased: It took ∼ 45 months for mean scores to cross baseline in 'Rotigotine-Rotigotine', and ∼ 21 months in 'Placebo-Rotigotine.' At the time mean UPDRS II + III had crossed baseline in 'Placebo-Rotigotine' (open-label week 84; ∼ 21 months), treatment difference (LS-mean) to 'Rotigotine-Rotigotine' change from baseline was -3.89 (95% CI -6.94, -0.84); p = 0.013.In this post hoc analysis, 6-month earlier initiation of rotigotine resulted in slower return to baseline mean UPDRS II + III; initiation of rotigotine in patients with minimal/no functional disability or impairment may lead to an extended benefit.

Background: The efficacy of rotigotine has been demonstrated in studies of patients with early (i.e. not receiving levodopa) and advanced (i.e. not adequately controlled on levodopa; average 2.5 h/day in ‘off’ state) Parkinson’s disease (PD). Objective: To further investigate the efficacy of rotigotine transdermal patch across different stages of PD symptom severity and functional disability, according to baseline Hoehn and Yahr (HY) staging. Methods: Post hoc analysis of six placebo-controlled studies of rotigotine in patients with early PD (SP506, SP512, SP513; rotigotine ≤8 mg/24 h) or advanced-PD (CLEOPATRA-PD, PREFER, SP921; rotigotine ≤16 mg/24 h). Data were pooled and analyzed according to baseline HY stage (1, 2, 3 or 4) for change from baseline to end of maintenance in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), UPDRS III (motor) and UPDRS II+III; statistical tests are exploratory. Results: Data were available for 2057 patients (HY 1 : 262; HY 2 : 1230; HY 3 : 524; HY 4 : 41). Patients at higher HY stages were older, had a longer time since PD diagnosis and higher baseline UPDRS II+III scores vs patients at lower HY stages. Rotigotine improved UPDRS II+III versus placebo for each individual HY stage (p

Preexisting renal impairment is an all-encompassing risk factor for radiocontrast-associated nephrotoxicity. Renal impairment appears to be associated with the inadequate production of renal prostaglandins at the critical time of radiocontrast administration and for a variable time period afterward. We prospectively studied 130 patients with chronic renal insufficiency (serum creatinine > or =1.5 mg/dL) who were undergoing radiocontrast administration. Using a double-blind, randomized, prospective technique, patients were assigned to either placebo or one of three prostaglandin E1 (PGE1) treatment groups (10, 20, or 40 ng/kg/min). Infusion was started 60 +/- 30 minutes before the administration of radiocontrast and was continued for a total of 6 hours. In the placebo group, radiocontrast administration resulted in a mean increase (+/- SD) in serum creatinine of 0.72 +/- 1.15 mg/dL at 48 hours. This increase was less in each of the PGE1 treatment groups after 48 hours, with a significant difference between placebo and the 20 ng/kg/min PGE1 group (P = 0.01). Using baseline adjusted means, analysis of covariance with baseline serum creatinine as the covariable demonstrated significant differences between the placebo and 20 ng/kg/min PGE1 group (P = 0.03) and between the placebo and 10 ng/kg/min PGE1 group P = 0.047). In a subgroup analysis of the diabetic patients, the increase in serum creatinine was less pronounced in the three PGE1 groups versus the placebo group, and the 20 ng/kg/min PGE1 group had the most favorable outcome. The parenteral administration of PGE1 immediately before radiocontrast exposure and continued for a period of 5 to 5.5 hours significantly reduced the elevation of serum creatinine poststudy. The most effective of the three PGE1 dosing regimens was 20 ng/kg/min.

The aim of this randomized study was to compare the reliability of the treadmill test at constant-load (C-test, 3 km/hr; fixed grade of 12%) recommended in Germany with that of the graded-exercise test (G-test, 3 km/hr; increase in grade of 3.5% every 3 minutes) propagated in the United States. In 50 patients with an absolute claudication distance (ACD) in the C-test of between 50 and 400 m, the two treadmill tests were carried out in randomized order on one and the same day, and repeated on 3 days within 1 week. For the initial claudication distance (ICD), the intraclass correlation was 0.88 in the C-test and 0.87 in the G-test. For the ACD the coefficients were identical at 0.91. The within-subject variation (CVwithin) in the C-test and G-test was 25% and 27% for the ICD and for the ACD 24% and 21%, respectively. The between-subject variation was very similar with 72% and 73% (ICD) and with 78% and 68% (ACD). However, in ACDs below 100 m and between 100 to 150 m, the C-test showed significantly smaller coefficients of variation than the G-test: 13% vs 81% and 14% vs 50%, respectively. In conclusion, the results showed that both C-test and G-test are equally well reproducible.

The computational problem of estimating measures of association and their asymptotic variances is addressed in the paper. The link between a special modeling approach for categorical data (GRIZZLE, STARMER & KOCH (1969)) and the estimation of measures of association under the multinomial sampling model is delineated. As a consequence, any statistical software program designed for the purpose of analyzing categorical data according to this modeling approach can be easily adapted to these specific estimation problems. This is explicitly outlined for a procedure of the SAS/STAT software (PROC CATMOD). The practical application of the method is illustrated for Cohen's κ, a popular measure of agreement between two different ratings.