Prism Clinical Research

ABSTRACTWe conducted a clinical trial to assess the safety and putative efficacy of an additional human rabies immune globulin (HRIG; KEDRAB) versus an older product (Comparator, HyperRAB S/D® [Grifols]) and determine whether HRIG interferes with development of endogenous antibodies versus Comparator, when each is given with an active rabies vaccine. This was a prospective, double-blind, single-period, non-inferiority study in which subjects were randomized (1:1) to a single dose (20 IU/kg) of HRIG or Comparator on day 0 and rabies vaccine (RabAvert® [GlaxoSmithKline]; 1 mL of ≥2.5 IU/mL) on days 0, 3, 7, 14, and 28. Anti-rabies antibodies were measured by rapid fluorescent focus inhibition test on day 14, and subjects were followed until day 185. Rabies virus neutralizing antibody (RVNA) titers ≥0.5 IU/mL were considered seroconversion putatively indicative of protection. The non-inferiority criterion was the lower limit of the 90% confidence interval (CI) >–10%, for the between-group difference in the proportion of subjects achieving RVNA ≥0.5 IU/mL. On day 14, 98.3% of 59 subjects in the HRIG group and 100% of 59 in the Comparator group had RVNA ≥0.5 IU/mL (difference between proportions – 1.8%; 90% CI, – 8.2, 3.1; non-inferiority criterion met). One subject in the HRIG group did not meet the seroconversion criteria for anti-rabies antibody, and one subject in the Comparator group showed an anamnestic response, with much higher than expected anti-rabies antibody levels at both baseline and on day 14. Thus, HRIG allows for prophylactic anti-rabies antibody titers and is non-inferior to Comparator, when administered with rabies vaccine.

IntroductionDifferences in immune characteristics, including immune gene expression by peripheral blood mononuclear cells (PBMCs), correlating with herpes labialis and good or poor immune control of herpes simplex virus type 1 (HSV‐1), and how these characteristics change after dosing with squaric acid dibutyl ester (SADBE), were investigated.MethodsPBMCs were collected from persons positive for IgG against HSV‐1 and having frequent, infrequent, or no herpes labialis outbreaks. The PBMCs were tested for proliferation against HSV‐1 and a fungal antigen (Candida) and immune gene expression in the presence of HSV‐1 and Candida. On day 1 after blood collection the subjects with frequent outbreaks were dosed topically on the arm once with SADBE, and their PBMCs were collected and tested 8 weeks later.ResultsThose with good immune control of their HSV‐1 infection (fewer outbreaks) differ from those with poorer immune control in these ways: (1) Greater PBMC proliferation in vitro to HSV‐1, HSV‐1‐infected cell extracts, and Candida considered together (P < 0.01). (2) Higher expression of IFNG and five other immune‐related genes (P < 0.05 for each) and lower expression of IL5 and two other immune‐related genes (P < 0.05 for each) in PBMCs in vitro stimulated with HSV‐1 virus. The subjects with frequent outbreaks were treated once with SADBE, and 56 days later the PBMCs of these subjects differed from PBMCs from the same subjects taken on day 1 before treatment in exactly the same ways listed above as differences between those with good and poor immune control of HSV‐1, and at the same levels of significance.ConclusionsHigher IFNG and lower IL5 expression by PBMCs in the presence of HSV‐1 correlate with fewer herpes labialis outbreaks, and a single topical dose of SADBE to the arm of subjects with frequent herpes labialis episodes improves immune response to HSV‐1.

Abstract Imprime PGG (Imprime), in combination with both tumor-targeting and anti-angiogenic antibodies, has shown promising efficacy in multiple phase 2 clinical trials. In numerous pre-clinical in vivo tumor models, Imprime also enhances the efficacy of immune checkpoint inhibitor antibodies in addition to tumor-targeting and anti-angiogenic antibodies. Imprime is a yeast-derived, soluble β-1,3/1,6 glucan that acts as a Pathogen Associated Molecular Pattern (PAMP) to trigger activation of innate immune effector cells (macrophages, monocytes, neutrophils, dendritic cells (DC)), which orchestrate a coordinated anti-cancer immune response with cells of the adaptive immune system. Ex vivo studies with human whole blood have shown that Imprime forms an immune complex with endogenous anti-beta glucan antibodies (ABA) to trigger a constellation of innate immune functions. These include complement activation via the classical complement pathway, select chemokine production, phenotypic activation and enhanced tumor cell killing by neutrophils and macrophages. Imprime also activates antigen-presenting cells (e.g. macrophages, DC), enabling T cell expansion and activation. In vivo, intravenous (IV) injection of Imprime in C57BL/6 mice increases select chemokine expression, triggers neutrophil and monocyte mobilization into circulation and secondary lymphoid organs, and also enhances DC maturation and antigen-specific T-cell priming. In this study, we show that the immunopharmacodynamic (IPD) responses elicited by IV administration of Imprime in healthy human subjects are consistent with the innate immune responses observed in ex vivo human and in vivo mouse studies. Healthy human volunteers (18-65 yr) were administered single (Cohort 1) or multiple (once weekly for 3 wks-Cohort 2) doses of Imprime PGG (4 mg/kg) by IV infusion over 2-3 hrs. Physical examination with vital signs, adverse event solicitation and timed blood sampling for IPD changes were performed. IPD endpoints included complement protein levels, circulating blood cell lineage counts, ABA concentrations, circulating immune complex (CIC) levels, cytokine and chemokine concentrations, as well as binding and activation of blood leukocytes. Cohort 1 and 2 results show that the complement activation proteins C5a and SC5b-9 were significantly increased in the plasma at the end of infusion (EOI) of Imprime. The formation of Imprime:ABA complexes was evident in a substantial drop of free ABA and a concomitant increase in CIC in the serum also at the EOI. IL-8 and MCP-1 were consistently detected between EOI and 1 hr post infusion. Additional chemokines, including MIP-1α, MIP-1β, and IP-10 were also detected in some of the subjects. A significant increase in the neutrophil and monocyte counts was seen in the blood after infusion. Cellular analyses showed Imprime binding to neutrophils, monocytes, and subsets of DC (classical and inflammatory) 15-30 mins after the start of infusion. Additionally, 24 hrs after completion of Imprime administration, a population of non-classical monocytes (CD14/CD16 positive), which are known to have higher antigen presentation capability and thus express higher levels of the activation markers CD86, PD-L1, and HLA-DR, was observed. Importantly, these IPD responses were evident only in subjects with higher ABA levels. Collectively, these data provide the first evidence that, when dosed IV in healthy human subjects, Imprime elicits a constellation of innate immune activating events that are consistent with efficacy in preclinical tumor models. Importantly, these human data also provide the first evidence linking pre-treatment ABA levels and Imprime induced IPD changes, suggesting the plausibility of using pre-treatment ABA levels in the selection of patients most likely to benefit from Imprime-based therapy. Citation Format: Nadine C. Ottoson, Richard D. Huhn, Jamie Lowe, Ben Harrison, Jose Iglesias, Blaine Rathmann, Takashi Kangas, Lindsay R. Wurst, Xiaohong Qiu, Anissa Chan, Adria Bykowski Jonas, Kathryn Fraser, Richard M. Walsh, Katie Ertelt, Steven M. Leonardo, Ross Fulton, Keith Gorden, Mark A. Matson, Mark Uhlik, Jeremy Graff, Nandita Bose. Imprime PGG, an intravenously administered beta glucan PAMP activates the innate immune system: A phase I clinical study to evaluate immunopharmacodynamic responses [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B008.

OBJECTIVE: To characterize the pharmacokinetic (PK) and safety profile of polyethylene glycol-interferon beta-1a (peginterferon beta-1a) delivered by a single-use autoinjector and pre-filled syringe (PFS) in healthy volunteers.

Linked Comment: Hackett. Int J Clin Pract 2012; 66: 113. To the Editor: We thank Dr Hackett for his interesting letter in response to our article. (1,2) The aim of the study was to determine the rate of newly detected underlying disease in men receiving their first (index) phosphodiesterase type 5 inhibitor (PDE5i) prescription. Records of eligible men were screened for new diagnostic codes during the first 3 months following PDE5i prescription using The Health Improvement Network (THIN) database in the UK. As outlined in the article, the prevalence of existing diagnoses was assessed in this observational database study by searching individual records for any diagnostic codes prior to the prescription date. In this context, the very low prevalence of hypogonadism recorded in this population is most likely related to the fact that testosterone is rarely measured in primary care and rarely prescribed. Consistent with the methodology used, it was not the aim of this study to detect the true prevalence of the disease. Further limitations inherent to any retrospective database study were discussed, and the important effect of under- and mis-reporting was specifically cited in the paper. GP practices supplying data to the THIN database are incentivised to supply accurate data regarding their prescriptions and why the drugs were prescribed. They are also incentivised to achieve targets in cardiovascular disease (CVD) and diabetes through the Quality Outcomes Framework (QOF); however, testosterone is not a QOF target (3). While both the EAU (4) and BSSM (5) guidelines recommend measuring testosterone in all patients with ED, their awareness is probably low in primary care. Worryingly, as mentioned in the article, urologists also seem reluctant to order laboratory tests in men presenting with ED (only 15% of 1590 urologists attending EAU conference in 2008 would do so) (6). As our study was simply to monitor the effect of current clinical assessment by GPs in conjunction with a PDE5i prescription, it does not provide evidence for low prevalence of hypogonadism, nor support the omission of testosterone measurements. In fact, we even added ‘a call to action’ that men are regularly asked about erection problems in clinical practice, given that a substantial proportion of men with ED do not seek medical advice or treatment. The opportunistic identification can be a trigger to assess and manage ED according to treatment recommendations. This may not only help address CVD risk factors but also help unveil testosterone deficiency syndrome and hypogonadism, which currently remain largely undetected (7). M. Kirby has received funding from the Pharmaceutical industry for research, advice, conference attendance and lecturing but no funding was received regarding this project.

Background/objective:Flu-like symptoms (FLS) are common side effects of interferon beta (IFNβ) therapy and can negatively affect the willingness of patients with multiple sclerosis to initiate therapy. Although dose titration is commonly used to reduce the severity and incidence of IFNβ-related FLS during treatment initiation, these benefits have not been confirmed in a well controlled study. The objective of this randomized, dose-blinded, parallel-group study was to assess the effect of dose titration on the severity and incidence of FLS during the initial 8 weeks of once-weekly intramuscular (IM) IFNβ-1a administration.Methods:Healthy volunteers were randomized 1:1:1 to one of three IM IFNβ-1a regimens: 3-week titration (weekly quarter-dose increments over 3 weeks to full dose [30 µg]); 6-week titration (biweekly quarter-dose increments over 6 weeks to full dose); or no titration (full dose over 8 weeks). At weekly clinic visits, the severity of each FLS was rated 1 hour pre-injection and 4–6 hours and 12–15 hours post-injection. Study endpoints included post-injection change in FLS severity and post-injection FLS incidence (percentage of subjects with a ≥2-point increase in total FLS severity score) at each time point.Clinical trial registration:Clinicaltrials.gov identifier: NCT01119677.Results:Of 234 subjects enrolled, 194 (83%) completed the study. At 8 weeks, FLS severity was significantly reduced at both post-injection time points with 3-week titration (76% reduction at 4–6 hours, p < 0.001; 37% reduction at 12–15 hours; p < 0.001) and 6-week titration (50% reduction at 4–6 hours, p < 0.001; 32% reduction at 12–15 hours; p = 0.002) compared with no titration. The incidence of FLS was also significantly reduced at both time points with both titration regimens. Safety profiles for both titration regimens were consistent with the current IM IFNβ-1a label. Study limitations included that there is currently no validated assessment tool for evaluating the severity of FLS, that the study enrolled healthy volunteers, that different proportions of females were randomized to the 3-week-titration group than to the 6-week and no-titration groups, and that evaluation of the potential impact of titration on symptoms occurring substantially later after injection was not part of the study protocol.Conclusion:Dose titration during initiation of IM IFNβ-1a reduces FLS severity and incidence in healthy volunteers compared with no titration.

Background Quercetin has been detected in a wide range of plant food products. It is believed that gut luminal concentrations of quercetin may be as much as 50-fold greater than those commonly attained in plasma. In vitro observations describe significant effects of various flavonoids, including quercetin, on several nutrient transporters that are active in human gut (SLGT1, GLUT2, GLUT5). This study was designed to assess the effect of orally administered quercetin on plasma glucose in patients (n=20) with type 2 diabetes. Methods A single-blind, placebo-controlled, within subject, repeated measures design was employed. Plasma glucose concentrations (0–4 hrs) during 75 gm oral glucose tolerance test were documented on two occasions; after concurrent consumption of oral quercetin placebo beverage at baseline and following the last of 5 consecutive days of oral quercetin (1500 mg) beverage. Glucose exposure estimates included; total (AUC0–4, hr*mg/dL) & incremental (iAUC0–4, hr*mg/dL) area-under-glucose-concentration time curve, partial areas, and individual glucose concentrations at key time points after glucose ingestion. Paired t-test and Wilcoxon match-pairs signed-ranks test were employed with p ≤ 0.05. Results No differences in plasma total or incremental glucose AUC (mean ± SD) were detected between placebo and quercetin exposure. AUC0–4 SD iAUC0–4 SD Placebo 871.9 269.6 309.5 158.9 quercetin 843.4 234.9 308.5 152.2 p-value 0.335 0.964 Additionally, no differences were detected in any of the other plasma glucose exposure estimates or concentrations. Conclusions Concurrent oral administration of quercetin (1500 mg) with glucose does not impact ultimate absorption of glucose in human patients with type 2 diabetes when absorption is assessed by measurement of changes in plasma glucose concentrations. Research was developed and funded by PepsiCo Global R&D.

Abstract Approximately 100 pressure pulse workovers have been performed on heavy oil wells in Canada since 1998. Analysis of a number of the wells shows varying degrees of success, but in general, the workovers have paid for themselves in almost all recent cases. Although there is insufficient information to fully prove hypotheses using statistical criteria, it appears that pressure pulse workovers have particular application in three situations: ▪In cases where the CHOPS well did not initially start producing sand during the primary completion attempts;▪In cases where the well became disconnected from the far-field pressure and gravity driving forces; and,▪In cases when it is desired to place a workover chemical in a well-dispersed fashion around a well. This article will review the physical mechanisms and drive energy sources that are believed to be responsible for CHOPS production; it will also present the physical processes that we believe occur during aggressive pressure pulse workovers around a heavy oil well.

Cross-national research into the care of people with severe mental illnesses is hampered by a lack of standardised measures. The European Psychiatric Services: Inputs Linked to Outcome Domains and Needs (EPSILON) Study is a European Union funded project within the BIOMED-2 programme. The project aims to develop standardised instruments to facilitate future cross-national research. To describe the aims, outcome measures, study sites and patient samples of the EPSILON Study. See companion papers in this supplement.