FGK Clinical Research

Primary axillary hyperhidrosis (PAHH) strongly affects the patient's quality of life. To date, topical treatment options are limited. One percent glycopyrronium bromide (GPB) showed promising efficacy and safety in a pivotal 4-week Phase 3a study. To assess efficacy and safety of topical 1% GPB cream in patients with severe PAHH in a long-term study of 72 weeks versus baseline. This was a long-term, open-label, Phase 3b trial for 72 weeks including 518 patients with severe PAHH. Patients were treated with 1% GPB cream once daily for 4 weeks, followed by a flexible dosing scheme (min. twice per week, max. once daily). Primary endpoint was the absolute change in sweat production from baseline to week 12. Further study endpoints included assessment of the severity of PAHH and the impact on quality of life. Total median sweat production decreased by 119.30 mg (-65.6%, both median) until week 12. Absolute change in sweat production from baseline to week 12 in logarithmic values was statistically significant (p< 0.0001). Patients' quality of life was improved at all study time points compared to baseline, as assessed by Hyperhidrosis Quality of Life Index and Dermatology Life Quality Index (p< 0.0001). Treatment was safe and locally well-tolerated with only few mild to moderate adverse drug reactions (ADRs). Dry mouth and application site erythema were the most common reported ADRs. Treatment with 1% GPB cream over 72 weeks significantly reduces sweat production and improves quality of life in patients with severe PAHH. One percent GPB cream is well-tolerated and provides an effective treatment option for long-term use in patients with severe PAHH.

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double‐blind, placebo‐controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double‐blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6‐year open‐label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg −53.9% [−62.5, −29.3], OCA 50 mg −37.2% [−54.8, −24.6]) compared to placebo (−0.8% [−6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open‐label extension treatment. OCA improved many secondary and exploratory endpoints (including γ‐glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. Conclusion: OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long‐term clinical outcomes. Pruritus increased dose‐dependently with OCA treatment. Biochemical improvements were observed through 6 years of open‐label extension treatment. (Hepatology 2018;67:1890‐1902).

Against the background of the continuously growing incidence rates of gerontopsychiatric disorders, their economic dimen-sions, and the effects on persons affected as well as their social environments, the present study focuses on an analysis of the services provided in acute psychiatric care settings for patients with dementia. RESULTS are based on secondary data. We aim to compare therapeutic service units of different clusters of occupational groups (physicians/psychologists, nurses/special therapists) for the ICD-10 diagnostic groups F00-F03 and G30 in the years 2010 (starting with July) and 2011. Main research question is how many patients are mappable with 'therapeutic units' (Therapieeinheiten, TE) of the operation and procedures catalogue (OPS). The present study is based on an analysis of the §21 KHEntgG data record of 35 acute psychiatric facilities. Data collection took place within the project "Versorgungsindikatoren für die Psychiatrie und Psychosomatik (VIPP)", "Supply indicators for psychiatric and psychosomatic settings". The data record implies statewide data of specialised hospitals, university hospitals and departments of psychiatry of the Federal Republic of Germany. In total, 5 111 cases were included in the analysis. Nurses and special therapists carried out significantly more therapeutic units in the main diagnoses groups (F01, F03 and G30) and the care groups (regular vs. intensive) than physicians and psychologists (p<0.05). It was not possible to map all patients with the use of therapeutic units (G30 78.8%, F01 83.4%, F03 81.2%). Mapping of patients was significantly higher in the intensive care compared to regular care in both occupational clusters (p<0.05). We demonstrated that the "therapeutic units" of the OPS codes are now used in the routine data (§21 KHEntgG), and that they are able to portray relevant aspects of non-medication therapeutic service. The present study provides a preliminary/exploratory overview on the services provided, mapped by therapeutic units. Future research should focus on the overlap between the category "therapeutic" units and the services actually provided.

Aims: Pegylated interferon (PEG-IFN) α and ribavirin (RBV) are the standard of care for hepatitis C treatment. The efficacy and safety of PEG-IFNα-2b and RBV was observed within a large German real life surveillance study.

To characterize the current economic burden of ventilator-associated pneumonia (VAP) and to determine which services increase the cost of VAP in North American hospitals. We performed a retrospective, matched cohort analysis of mechanically ventilated patients enrolled in the North American Silver-Coated Endotracheal Tube (NASCENT) study, a prospective, randomized study conducted from 2002 to 2006 in 54 medical centers, including 45 teaching institutions (83.3%). Case patients with microbiologically confirmed VAP (n = 30)were identified from 542 study participants with claims data and were matched by use of a primary diagnostic code, and subsequently by the Acute Physiology and Chronic Health Evaluation II score, to control patients without VAP (n = 90). Costs were estimated by applying hospital-specific cost-to-charge ratios based on all-payer inpatient costs associated with VAP diagnosis-related groups. Median total charges per patient were $198,200 for case patients and $96,540 for matched control patients (P < .001); corresponding median hospital costs were $76,730 for case patients and $41,250 for control patients (P = .001). After adjusting for diagnosis-related group payments, median losses to hospitals were $32,140 for case patients and $19,360 for control patients (P = .151). The median duration of intubation was longer for case patients than for control patients (10.1 days vs 4.7 days; P < .001), as were the median duration of intensive care unit stay (18.5 days vs 8.0 days; P < .001) and the median duration of hospitalization (26.5 days vs 14.0 days; P < .001). Examples of services likely to be directly related to VAP and having higher median costs for case patients were hospital care (P < .05) and respiratory therapy (P < .05). VAP was associated with increased hospital costs, longer duration of hospital stay, and a higher number of hospital services being affected, which underscores the need for bundled measures to prevent VAP. NASCENT study ClinicalTrials.gov Identifier: NCT00148642.

Tumour invasion and metastasis depend on the capacity of tumour cells to coordinate various biological processes such as detachment of cells from their original localisation, cancer cell migration, invasion of cancer cells into surrounding tissue, access to blood and lymphatic vessels and adhesion to and invasion through the endothelium, allowing colonisation at distant sites of the organism. This complex scenario requires the concerted and regulated expression of extracellular proteolytic systems, integrins and adhesion proteins. Degradation of proteins in basement membranes and extracellular matrix is the prerequisite for the invasion of cells and the formation of metastases. This is mediated by various extracellular proteolytic enzymes including serine proteinases, metalloproteinases and cysteine proteinases [1]. There is abundant experimental evidence that the plasminogen activator system plays an essential role in these processes [1,2,3,4,5,6,7,8]. It consists of two serine proteinases, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), the cell surface uPA receptor (uPAR) and the plasminogen activator inhibitors 1 and 2 (PAI-1, PAI-2). uPA is agreed to be the enzyme with the major influence on cancer-related processes, whereas the primary role of tPA is the generation of plasmin for fibrinolysis of blood vessels [9]. Besides its proteolytic activity, uPA in concert with uPAR also mediates mitogenic, adhesive and migratory processes [10]. Clinical studies have demonstrated the relevance of uPA, uPAR and PAI-1 in malignant tumours such as breast, ovary, cervical, upper urinary, gastrointestinal, lung, prostate and other cancers. Elevated levels of these factors correlate with increased malignancy and poor patient outcome [1, 7, 11, 12]. For head and neck squamous cell carcinoma (HNSCC) the role of the uPA system has been extensively investigated [13,14,15,16,17]. In tumour lysates, it has been demonstrated that both uPA and PAI-1 may play a specific role in the process of invasion and metastasis and might also be of prognostic value in this carcinoma [18, 19]. Recently, Wilex developed a serine protease inhibitor of the uPA system, the intravenous drug WX-UK1, and its new orally administered pro-drug WX-671 to treat cancer. Once WX-671 is absorbed, the hydroxyamidino function is reductively converted to the amidino function, thereby generating pharmacologically active WX-UK1. In rat, dog and monkey, WX-671 is effectively absorbed, although with varying rates between species, and readily metabolised to WX-UK1. In rat models, WX-671 has been shown to be efficacious at inhibiting tumour growth and spread. For clinical testing in man, hard gelatine capsules are available that contain WX-671 hydrogen sulphate equivalent to 50 mg and 200 mg WX-671 (free base). The aim of this study was to evaluate the pharmacokinetics of both the oral pro-drug WX-671 and the metabolite WX-UK1 in human tissue and plasma of patients with HNSCC. In addition, the safety and tolerability as well as the effects on the uPA system of WX-671 were assessed.

Hintergrund: Pegyliertes Interferon (PEG-IFN alfa) und Ribavirin (RBV) sind die Standardkombinationsbehandlung für eine Therapie der chronischen Hepatitis C. Wirksamkeit und Sicherheit von PEG-IFN alfa–2b und RBV wurden im Rahmen einer großen deutschen Beobachtungsstudie ermittelt. Methoden: Zwischen 9/2003 und 4/2007 haben 280 aktive Zentren 3948 HCV Patienten.behandelt. Davon waren 96 Patienten (2.4%) mit HBV und 80 Patienten (2.0%) mit HIV koinfiziert. Die Datenanalyse basiert auf statistischen Standardverfahren und 95%igen zweiseitigen Konfidenzintervallen. Dauerhaftes virologisches Ansprechen (sustained virological response=SVR) ist definiert als HCV-RNA-Negativität nach 24 Wochen Beobachtungszeit über das Behandlungsende hinaus. Bei 6% (n=230) aller Patienten lag eine Leberzirrhose vor, wobei davon 1% (n=1) der HCV/HBV koinfizierten Patienten und 6% (n=5) der HCV/HIV Koinfizierten betroffen waren. 90% aller Patienten (n=3539) erhielten PEG-IFN-alfa–2b und RBV als Ersttherapie, wobei dieser Anteil mit 90% behandlungsnaïver Patienten in der Gruppe mit HCV/HBV Koinfektion (n=86) und in der Gruppe mit HCV/HIV Koinfizierten (n=77) identisch war. In dieser Analyse sind die Patienten erfasst, die bisher die geplante Therapiedauer und sechs Monate Nachbeobachung erreicht haben (n=1974). Ergebnisse: Die SVR-Rate ist 58.1% (n=1146), 56.5% (n=26) für Koinfektion HCV/HBV (n=46) und 45.7% (n=16) für HCV/HIV Koinfektion. Die Relapse Raten sind 13.0% (n=257) bei allen Patienten, 8.7% (n=4) für HCV/HBV und 8.6% (n=3) für HCV-HIV-Koinfizierte. Der Anteil aller Patienten, die nicht auf die Behandlung ansprachen, ist 17.7% (n=350) verglichen mit 19.6% (n=9) für HCV/HBV und 28.6% (n=10) für HCV/HIV Koinfizierte. Zusammenfassung: Die vorläufigen Ergebnisse für schwer zu behandelnde koinfizierte HCV-Patienten sind speziell für HCV/HBV Patienten ermutigend und vergleichbar mit HCV-Monoinfizierten. Basierend auf kleinen Patientenzahlen zeichnet sich für HCV-HIV-Koinfizierte eine geringere Aussicht auf SVR und ein höheres Risiko zu primärem Nichtansprechen auf die Therapie ab.