Diurnal variation in DLCO and non-standardized study procedures may cause a false positive safety signal in clinical trials.

Diffusing capacity for carbon monoxide (DLCO) was measured in a phase I single ascending dose study after inhalation of AZD8154 or placebo in healthy participants at baseline (DLCOBaseline) and follow-up (DLCOFollow-up) 6 days after dosing. Initially, DLCOFollow-up timepoint was 2 h earlier than the DLCOBaseline timepoint and clinically significant decreases in DLCOFollow-up (absolute change up to 19% from baseline and DLCO%predicted values less than 70) were observed then. The observed reduction in DLCOFollow-up was confirmed as a false positive finding after alignment of DLCO timings. As a consequence, when DLCO is used in clinical studies, measurements should be strictly standardized in relation to time of the day.

Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): A phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine.

An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 µg). All vaccines were well tolerated, apart from in the TLR7a 100 µg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56-81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 µg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination.

Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes.

Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4-24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis.

GP2017, an adalimumab biosimilar: pharmacokinetic similarity to its reference medicine and pharmacokinetics comparison of different administration methods.

Background: To compare the pharmacokinetics of Sandoz biosimilar adalimumab (GP2017) with reference adalimumab (Humira) in healthy volunteers (PK similarity study) and to compare the pharmacokinetics of GP2017 administered by autoinjector (AI) or prefilled syringe (PFS; delivery study). Methods: Healthy male subjects were randomized to receive a single 40 mg subcutaneous injection of GP2017, US-licensed or EU-authorized reference adalimumab (US/EU-Humira; PK similarity study) or a single 40 mg subcutaneous injection of GP2017 via AI or PFS (delivery study). Pharmacokinetics, safety, and immunogenicity were assessed over 72 days post-injection. Results: The geometric mean ratios (90% confidence intervals) for Cmax and AUC0-inf were 1.05 (0.99-1.11) and 1.04 (0.96-1.13) for GP2017/EU-Humira and 1.00 (0.94-1.06) and 1.08 (1.00-1.18) for GP2017/US-Humira, all within the prespecified margin of 0.80-1.25 (PK similarity study). Pharmacokinetic parameters of GP2017 matched between AI and PFS (delivery study). Safety and immunogenicity were similar across groups in both studies. Conclusion: PK similarity between GP2017, EU- and US-Humira was demonstrated. The safety profile of GP2017 was consistent with previous reports for Humira. These results contribute to the 'totality-of-the-evidence' supporting biosimilarity of GP2017 to Humira. PK and tolerability were equivalent for GP2017 dosed by AI or PFS. Trial registration: PK similarity study EudraCT no. 2015-000579-28; Delivery study: EudraCT no. 2014-002879-29.

Safety, tolerability, and pharmacokinetics of the novel αv-integrin antibody EMD 525797 (DI17E6) in healthy subjects after ascending single intravenous doses.

PURPOSE: We evaluated the safety, tolerability, and pharmacokinetics (PK) of EMD 525797 (DI17E6), a humanized monoclonal antibody targeting αv-integrins, in healthy subjects. METHODS: In this first-in-human, double-blind, placebo-controlled, randomized Phase 1 study, healthy male volunteers were consecutively assigned to 6 ascending single-dose cohorts of 35, 100, 250, 500, 1000, or 1500 mg. Per dose cohort, EMD 525797 or placebo was administered over 1 h as an intravenous 250-mL infusion to 6 and 3 volunteers, respectively. Escalation to the next dose level was based on evaluation of safety, tolerability, and PK data. RESULTS: Fifty-five subjects (aged 18-45 years) were randomized. Twenty-seven of 37 (73 %) subjects receiving EMD 525797 reported a total of 61 adverse events (AEs), including 38 events (in 17 subjects) considered by the investigator to be treatment related. A total of 35 AEs were reported by 14 of 18 (78 %) placebo-treated subjects. The most commonly occurring AEs were gastrointestinal disorders, abnormal laboratory values, and increased or decreased biochemistry and/or hematology values, as well as headaches, which occurred at a slightly higher frequency in the EMD 525797 group compared with placebo. There were no serious AEs or deaths. EMD 525797 PK appeared to be dose dependent, especially at lower doses. CONCLUSION: Ascending single doses of EMD 525797 were shown to be safe and well tolerated. No safety concerns were identified. This study supports the ongoing investigation of EMD 525797.

Circulating adipokines and the protective effects of hyperinsulinemia in inflammatory bowel disease.

OBJECTIVE: Adipokines are fat-derived hormones and cytokines with immune-modulating and metabolic properties. Most of them are associated with insulin resistance. The aim of the present investigation was to evaluate circulating levels of adipokines and glucose homeostasis in patients with inflammatory bowel disease (IBD) and to evaluate possible associations with the course and characteristics of the disease. METHODS: Serum leptin, resistin, visfatin, retinol-binding protein-4, adiponectin, glucose, insulin, and inflammatory parameters were analyzed in 93 patients with inactive IBD (49 with Crohn's disease [CD], 44 with ulcerative colitis [UC]), 35 patients with active IBD (18 with CD, 17 with UC), and 37 age- and body mass index-matched healthy controls. Ninety-two patients were followed for 6 mo. RESULTS: Leptin was similar in patients with IBD and controls, whereas resistin and visfatin were increased in patients with active disease but not in those in remission. In active and inactive disease, adiponectin was decreased (P < 0.001) and retinol-binding protein-4 was increased (P < 0.001) compared with controls. About 60% of patients with IBD showed increased levels of insulin, whereas serum glucose remained normal, resulting in increased homeostasis model assessment values in most patients. Hyperinsulinemia was associated with the decrease in adiponectin (r = -0.572, P < 0.001) and proved to be an independent protective factor for 6-mo maintenance of remission (P = 0.016). CONCLUSION: IBD led to largely similar alterations in circulating adipokines and hyperinsulinemia in patients with CD and those with UC. The unexpected protective effect of hyperinsulinemia on relapse rate denotes the role of the metabolic-inflammatory response as a modulator in IBD.

Malnutrition and impaired muscle strength in patients with Crohn's disease and ulcerative colitis in remission.

OBJECTIVE: This prospective, controlled, and multicentric study evaluated nutritional status, body composition, muscle strength, and quality of life in patients with inflammatory bowel disease in clinical remission. In addition, possible effects of gender, malnutrition, inflammation, and previous prednisolone therapy were investigated. METHODS: Nutritional status (subjective global assessment [SGA], body mass index, albumin, trace elements), body composition (bioelectrical impedance analysis, anthropometry), handgrip strength, and quality of life were assessed in 94 patients with Crohn's disease (CD; 61 female and 33 male, Crohn's Disease Activity Index 71 +/- 47), 50 patients with ulcerative colitis (UC; 33 female and 17 male, Ulcerative Colitis Activity Index 3.1 +/- 1.5), and 61 healthy control subjects (41 female and 20 male) from centers in Berlin, Vienna, and Bari. For further analysis of body composition, 47 well-nourished patients with inflammatory bowel disease were pair-matched by body mass index, sex, and age to healthy controls. Data are presented as median (25th-75th percentile). RESULTS: Most patients with inflammatory bowel disease (74%) were well nourished according to the SGA, body mass index, and serum albumin. However, body composition analysis demonstrated a decrease in body cell mass (BCM) in patients with CD (23.1 kg, 20.8-28.7, P = 0.021) and UC (22.6 kg, 21.0-28.0, P = 0.041) compared with controls (25.0 kg, 22.0-32.5). Handgrip strength correlated with BCM (r = 0.703, P = 0.001) and was decreased in patients with CD (32.8 kg, 26.0-41.1, P = 0.005) and UC (31.0 kg, 27.3-37.8, P = 0.001) compared with controls (36.0 kg, 31.0-52.0). The alterations were seen even in patients classified as well nourished. BCM was lower in patients with moderately increased serum C-reactive protein levels compared with patients with normal levels. CONCLUSION: In CD and UC, selected micronutrient deficits and loss of BCM and muscle strength are frequent in remission and cannot be detected by standard malnutrition screening.

Altered status of antioxidant vitamins and fatty acids in patients with inactive inflammatory bowel disease.

BACKGROUND & AIMS: Data regarding the nutritional status, antioxidant compounds and plasma fatty acid (FA) composition in inactive IBD are conflicting. We compared plasma levels of antioxidants and FA of patients with inactive IBD with active IBD and controls. METHODS: Plasma levels of vitamin C, vitamin E, carotenoids, saturated, monounsaturated and polyunsaturated FA, inflammatory markers and nutritional status were determined after an overnight fast in 132 patients with quiescent IBD (40.6+/-13.2 years, 87F/45M), 35 patients with active disease (37.9+/-12.1 years, 25F/10M) and 45 age- and BMI-matched healthy controls (38.1+/-10.5 years, 39F/6M). Results are expressed as mean+/-SD or median [25th percentile;75th percentile]. RESULTS: Body mass index (BMI) was normal in inactive (23.9+/-4.7 kg/m(2)), active IBD (22.7+/-4.2 kg/m(2)) and controls (22.3+/-1.9 kg/m(2)). Compared with controls patients with quiescent IBD showed significantly decreased plasma levels of carotenoids (1.85 [1.37;2.56] vs 1.39 [0.88;1.87] micromol/L) and vitamin C (62.3 [48.7;75.0] vs 51.0 [36.4;77.6] micromol/L), increased levels of saturated FA (3879 [3380;4420] vs 3410 [3142;3989] micromol/L) and monounsaturated FA (2578 [2258;3089] vs 2044 [1836;2434] micromol/L) and similar levels of vitamin E and polyunsaturated FA. Results in active disease were similar to inactive disease. CONCLUSION: This study shows that antioxidant status and FA profile in a larger population of IBD patients are disturbed independently from disease activity and despite normal overall nutritional status.