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Risankizumab is a humanised IgG1 monoclonal antibody that binds to the p19 subunit of interleukin-23, inhibiting this key cytokine and its role in psoriatic inflammation. We aimed to assess the efficacy and safety of risankizumab compared with placebo or ustekinumab in patients with moderate-to-severe chronic plaque psoriasis. UltIMMa-1 and UltIMMa-2 were replicate phase 3, randomised, double-blind, placebo-controlled and active comparator-controlled trials done at 139 sites in Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Japan, Mexico, Poland, Portugal, South Korea, Spain, and the USA. Eligible patients were 18 years or older, with moderate-to-severe chronic plaque psoriasis. In each study, patients were stratified by weight and previous exposure to tumour necrosis factor inhibitor and randomly assigned (3:1:1) by use of interactive response technology to receive 150 mg risankizumab, 45 mg or 90 mg ustekinumab (weight-based per label), or placebo. Following the 16-week double-blind treatment period (part A), patients initially assigned to placebo switched to 150 mg risankizumab at week 16; other patients continued their originally randomised treatment (part B, double-blind, weeks 16–52). Study drug was administered subcutaneously at weeks 0 and 4 during part A and at weeks 16, 28, and 40 during part B. Co-primary endpoints were proportions of patients achieving a 90% improvement in the Psoriasis Area Severity Index (PASI 90) and a static Physician's Global Assessment (sPGA) score of 0 or 1 at week 16 (non-responder imputation). All efficacy analyses were done in the intention-to-treat population. These trials are registered with ClinicalTrials.gov, numbers NCT02684370 (UltIMMa-1) and NCT02684357 (UltIMMa-2), and have been completed. Between Feb 24, 2016, and Aug 31, 2016, 506 patients in UltIMMa-1 were randomly assigned to receive 150 mg risankizumab (n=304), 45 mg or 90 mg ustekinumab (n=100), or placebo (n=102). Between March 1, 2016, and Aug 30, 2016, 491 patients in UltIMMa-2 were randomly assigned to receive 150 mg risankizumab (n=294), 45 mg or 90 mg ustekinumab (n=99), or placebo (n=98). Co-primary endpoints were met for both studies. At week 16 of UltIMMa-1, PASI 90 was achieved by 229 (75·3%) patients receiving risankizumab versus five (4·9%) receiving placebo (placebo-adjusted difference 70·3% [95% CI 64·0–76·7]) and 42 (42·0%) receiving ustekinumab (ustekinumab-adjusted difference 33·5% [22·7–44·3]; p<0·0001 vs placebo and ustekinumab). At week 16 of UltIMMa-2, PASI 90 was achieved by 220 (74·8%) patients receiving risankizumab versus two (2·0%) receiving placebo (placebo-adjusted difference 72·5% [95% CI 66·8–78·2]) and 47 (47·5%) receiving ustekinumab (ustekinumab-adjusted difference 27·6% [16·7–38·5]; p<0·0001 vs placebo and ustekinumab). In UltIMMa-1, sPGA 0 or 1 at week 16 was achieved by 267 (87·8%) patients receiving risankizumab versus eight (7·8%) receiving placebo (placebo-adjusted difference 79·9% [95% CI 73·5–86·3]) and 63 (63·0%) receiving ustekinumab (ustekinumab-adjusted difference 25·1% [15·2–35·0]; p<0·0001 vs placebo and ustekinumab). In UltIMMa-2, 246 (83·7%) patients receiving risankizumab versus five (5·1%) receiving placebo (placebo-adjusted difference 78·5% [95% CI 72·4–84·5]) and 61 (61·6%) receiving ustekinumab achieved sPGA 0 or 1 at week 16 (ustekinumab-adjusted difference 22·3% [12·0–32·5]; p<0·0001 vs placebo and ustekinumab). The frequency of treatment-emergent adverse events in UltIMMa-1 and UltIMMa-2 was similar across risankizumab (part A: 151 [49·7%] of 304 and 134 [45·6%] of 294; part B: 182 [61·3%] of 297 and 162 [55·7%] of 291), placebo (part A: 52 [51·0%] of 102 and 45 [45·9%] of 98), ustekinumab (part A: 50 [50·0%] of 100 and 53 [53·5%] of 99; part B: 66 [66·7%] of 99 and 70 [74·5%] of 94), and placebo to risankizumab (part B: 65 [67·0%] of 97 and 61 [64·9%] of 94) treatment groups throughout the study duration. Risankizumab showed superior efficacy to both placebo and ustekinumab in the treatment of moderate-to-severe plaque psoriasis. Treatment-emergent adverse event profiles were similar across treatment groups and there were no unexpected safety findings. AbbVie and Boehringer Ingelheim.

In animal models, immunity to mosquito salivary proteins protects animals against mosquito-borne disease. These findings provide a rationale to vaccinate against mosquito saliva instead of the pathogen itself. To our knowledge, no vector salivary protein-based vaccine has been tested for safety and immunogenicity in humans. We aimed to assess the safety and immunogenicity of Anopheles gambiae saliva vaccine (AGS-v), a peptide-based vaccine derived from four A gambiae salivary proteins, in humans. In this randomised, placebo-controlled, double-blind, phase 1 trial, participants were enrolled at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Participants were eligible if they were healthy adults, aged 18–50 years with no history of severe allergic reactions to mosquito bites. Participants were randomly assigned (1:1:1), using block randomisation and a computer-generated randomisation sequence, to treatment with either 200 nmol of AGS-v vaccine alone, 200 nmol of AGS-v with adjuvant (Montanide ISA 51), or sterile water as placebo. Participants and clinicians were masked to treatment assignment. Participants were given a subcutaneous injection of their allocated treatment at day 0 and day 21, followed by exposure to feeding by an uninfected Aedes aegypti mosquito at day 42 to assess subsequent risk to mosquito bites in a controlled setting. The primary endpoints were safety and immunogenicity at day 42 after the first immunisation. Participants who were given at least one dose of assigned treatment were assessed for the primary endpoints and analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03055000, and is closed for accrual. Between Feb 15 and Sept 10, 2017, we enrolled and randomly assigned 49 healthy adult participants to the adjuvanted vaccine (n=17), vaccine alone (n=16), or placebo group (n=16). Five participants did not complete the two-injection regimen with mosquito feeding at day 42, but were included in the safety analyses. No systemic safety concerns were identified; however, one participant in the adjuvanted vaccine group developed a grade 3 erythematous rash at the injection site. Pain, swelling, erythema, and itching were the most commonly reported local symptoms and were significantly increased in the adjuvanted vaccine group compared with both other treatment groups (nine [53%] of 17 participants in the adjuvanted vaccine group, two [13%] of 16 in the vaccine only group, and one [6%] of 16 in the placebo group; p=0·004). By day 42, participants who were given the adjuvanted vaccine had a significant increase in vaccine-specific total IgG antibodies compared with at baseline than did participants who were give vaccine only (absolute difference of log10-fold change of 0·64 [95% CI 0·39 to 0·89]; p=0·0002) and who were given placebo (0·62 [0·34 to 0·91]; p=0·0001). We saw a significant increase in IFN-γ production by peripheral blood mononuclear cells at day 42 in the adjuvanted vaccine group compared with in the placebo group (absolute difference of log10 ratio of vaccine peptide-stimulated vs negative control 0·17 [95% CI 0·061 to 0·27]; p=0·009) but we saw no difference between the IFN-γ production in the vaccine only group compared with the placebo group (0·022 [–0·072 to 0·116]; p=0·63). AGS-v was well tolerated, and, when adjuvanted, immunogenic. These findings suggest that vector-targeted vaccine administration in humans is safe and could be a viable option for the increasing burden of vector-borne disease. Office of the Director and the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

Determining feasibility and tolerability of large volume viscous subcutaneous injection may enable optimized, intuitive delivery system design. A translational early feasibility clinical study examined large volume subcutaneous injection viability, tolerability, acceptability, tissue effects and depot location for ~1, 8, and 20 cP injections at volumes up to 10 ml in the abdomen and 5 ml in the thigh in 32 healthy adult subjects. A commercial syringe pump system delivered 192 randomized, constant rate (20 µl/s) injections (6/subject) with in‐line injection pressure captured versus time. Deposition location was qualified via ultrasound. Tissue effects and pain tolerability were monitored through 2 hours post‐injection with corresponding Likert acceptability questionnaires administered through 72 hours. All injection conditions were feasible and well‐tolerated with ≥79.3% favorable subject responses for injection site appearance and sensation immediately post‐injection, increasing to ≥96.8% at 24 hours. Mean subject pain measured via 100 mm visual analog scale increased at needle insertion (6.9 mm, SD 10.8), peaked during injection (26.9 mm, SD 21.7) and diminished within 10 minutes post‐removal (1.9 mm, SD 4.2). Immediate injection site wheal (90.9%) and erythema (92.6%) formation was observed with progressive although incomplete resolution through 2 hours (44.6% and 11.4% remaining, respectively). Wheal resolution occurred more rapidly at lower viscosities. Most subjects (64.5%) had no preference between abdomen and thigh. Correlations between tissue effects, injection pressure and pain were weak (Pearson’s rho ± 0–0.4). The large volume injections tested, 1–20 cP viscosities up to 10 ml in the abdomen and 5 ml in the thigh, are feasible with good subject acceptability and rapid resolution of tissue effects and pain.

Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS. In this multicentre, randomised, comparative, parallel-group, open-label study, patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were randomised to receive 44 μg subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse. A subpopulation of 460 patients (230 from each group) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume. Treatments were assigned by a computer-generated randomisation list that was stratified by centre. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00078338. Between February and December, 2004, 764 patients were randomly assigned: 386 to interferon beta-1a and 378 to glatiramer acetate. After 96 weeks, there was no significant difference between groups in time to first relapse (hazard ratio 0·94, 95% CI 0·74 to 1·21; p=0·64). Relapse rates were lower than expected: 258 patients (126 in the interferon beta-1a group and 132 in the glatiramer acetate group) had one or more relapses (the expected number was 460). For secondary outcomes, there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions, although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions (0·24 vs 0·41 lesions per patient per scan, 95% CI −0·4 to 0·1; p=0·0002). Safety and tolerability profiles were consistent with the known profiles for both compounds. The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks. There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome. The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity, which is an important consideration for ongoing and future trials in patients with RRMS. EMD Serono; Pfizer.

The licensed live, attenuated varicella-zoster virus vaccine prevents herpes zoster in adults older than 50 years. We aimed to determine whether intradermal administration of zoster vaccine could enhance vaccine immunogenicity compared with conventional needle subcutaneous administration. In this randomised, dose-ranging study, adults aged 50 years or older who had a history of varicella or who had resided in a country with endemic varicella-zoster virus infection for 30 years or more were eligible. Participants received the approved full or a 1/3 dose of zoster vaccine given subcutaneously or one of four intradermal doses (full, 1/3, 1/10, or 1/27 dose) using the MicronJet600 device. The two subcutaneous doses and the four intradermal doses were randomised (1·5:1:1:1:1:1) by computer generated sequence with randomisation stratified by age (50–59 years or 60 years or older). The primary immunogenicity endpoint was the change from baseline in IgG antibody to varicella-zoster virus-specific glycoproteins (gpELISA) measured at 6 weeks. All patients were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01385566. Between Sept 2, 2011, and Jan 13, 2012, 224 participants were enrolled from three clinics in the USA and 223 were randomly assigned: 52 to receive the full dose subcutaneous zoster vaccine, 34 to receive the 1/3 dose subcutaneous zoster vaccine, 34 to receive the full dose intradermal zoster vaccine, 35 to receive the 1/3 dose intradermal zoster vaccine, 34 to receive the 1/10 dose intradermal zoster vaccine, and 34 to receive the 1/27 dose intradermal zoster vaccine. Full dose zoster vaccine given subcutaneously resulted in a gpELISA geometric mean fold-rise (GMFR) of 1·74 (90% CI 1·48–2·04) at 6 weeks post-vaccination compared with intradermal administration which resulted in a significantly higher gpELISA GMFR of 3·25 (2·68–3·94; p<0·0001), which also remained high at 18 months. An apparent dose–response relation was observed with intradermal administration (1/3 dose subcutaneous GMFR 1·64 [90% CI 1·36–1·99], 1/3 dose intradermal 2·58 (2·13–3·13), 1/10 dose intradermal 2·22 [1·83–2·69], and 1/27 dose intradermal 1·64 [1·35–2·00]). Each partial dose of zoster vaccine given intradermaly had a gpELISA GMFR comparable to that of full dose zoster vaccine given subcutaneously. Transient erythema and induration were more common after intradermal administration (31% erythema for full subcutaneous dose and 77% for intradermal dose). Intradermal zoster vaccine showed a greater increase in varicella-zoster virus gpELISA antibody compared with subcutaneous zoster vaccine at comparable doses. Larger and longer studies of intradermal administration of live, attenuated zoster vaccine are needed to provide convincing evidence of improved cell mediated immunity. Merck & Co Inc.

OBJECTIVE: To compare use of continuous glucose monitoring in subjects with type 1 diabetes on multiple daily injection (MDI) therapy versus continuous subcutaneous insulin infusion (CSII) therapy for 6 months. RESEARCH DESIGN AND METHODS: Sixty type 1 diabetic adults with similar baseline characteristics, using either MDI (n = 30) or CSII (n = 30) therapy, were enrolled in this 6-month prospective study. Subjects were instructed to wear the DexCom SevenPLUS continuous glucose monitor at all times throughout the study. All subjects were initially blinded from the continuous glucose monitoring (CGM) glucose data. After 4 weeks of blinded CGM use, the CGM was unblinded, making glucose data available to the patient. The CGM remained in the unblinded state for the remainder of the study (20 weeks). Clinic visits occurred every 4 weeks, at which time A1C values were collected and CGM data were downloaded. RESULTS: Mean baseline (± SD) A1C was 7.61 (± 0.76) and 7.63 (± 0.68) for CSII and MDI, respectively (P > 0.05). Without any significant therapy change, A1C decrease at 12 weeks was similar in both groups (P = 0.03). When compared with the blinded phase, unblinded use of CGM was associated with similar but significant reductions in glycemic control and variability parameters. In addition, both therapy groups had similar changes in mean glucose and glucose variability indexes at 3 and 6 months (ITT analysis, P > 0.05). Predefined per protocol analysis (sensor use at least 6 days/week) showed greater improvement in time spent in target range glycemia, 3.9-10.0 mmol/L (70-180 mg/dL), in the CSII group. CONCLUSIONS: We conclude that CGM provides similar benefits in glucose control for patients using MDI or CSII therapy.

Pen needles (PNs) are essential for insulin injections using pen devices. PN characteristics affect patients’ injection experience. The goal of this study was to evaluate the impact of a new extra-thin wall (XTW) PN versus usual PNs on overall patient preference, ease of injection, perceived time to complete the full dose, thumb button force to deliver the injection, and dose delivery confidence in individuals with diabetes mellitus (DM). Subjects injected insulin with the KwikPenTM (Eli Lilly and Company, Indianapolis, Indiana), SoloSTAR® (sanofi-aventis U.S. LLC, Bridgewater, New Jersey), and FlexPen® (Novo Nordisk A/S, Bagsvaerd, Denmark) insulin pens, and included some with impaired hand dexterity. We first performed quantitative testing of XTW and comparable PNs with the 3 insulin pens for thumb force, flow rate, and time to deliver medication. A prospective, randomized, 2-period, open-label, crossover trial was then conducted in patients aged 35 to 80 years with type 1 or type 2 DM who injected insulin by pen for ≥2 months, with at least 1 daily dose ≥10 U. Patients who used 4- to 8-mm length PNs with 31- to 32-G diameter were randomly assigned to use their current PN or the same/similar size XTW PN at home for ~1 week and the other PN the second week. They completed several comparative 150-mm visual analog scales and direct questions at the end of period 2. XTW PNs had statistically significant better performance for each studied PN characteristic (thumb force, flow, and time to deliver medication) for all pens combined and each individual pen brand (all, P ≤ 0.05). Of 216 patients randomized to study groups (80, SoloSTAR; 77, FlexPen; 59, KwikPen), 209 completed both periods; 198 were evaluable. Baseline characteristics revealed a mean (SD) age of 60.8 (9.3) years, insulin pen use duration of 4.3 (4.1) years, and mean total daily dose of 75.1 (52.3) U (range, 10–420 U). Approximately 50% of patients were female; 81.5% were white and 14.8% were black; and 89.8% had type 2 DM. Nearly 99% used a single PN: 8 mm, 49.5%; 5 mm, 24.1%; 6 mm, 14.4%; and 4 mm, 12.0%. Patients rated the XTW PNs (mean [95% CI]) as preferable by a mean of 31.9 mm (27.2–36.6), P < 0.001; XTW PNs required less thumb force, less time to inject the dose, and were rated as providing greater confidence in full dose delivery by 28.4 mm (23.7–33.2), 21.7 mm (17.0–26.4), and 24.4 mm (19.7–29.1), respectively; all, P < 0.001. Results were similar for each of the 3 pens, those with impaired hand dexterity, and for all users of 4-mm PNs. Skin leakage and insulin dripping from the needle tip were rated as less frequent with the XTW PNs (P < 0.05). The most common adverse events were hypoglycemia in 8.3% and 6.0% of patients using XTW PNs and current PNs (P = NS), respectively; hyperglycemia occurred in 2.9% and 4.1% (P = NS). None of the adverse events was serious or considered device related. XTW PNs were preferred overall, rated as requiring less time and less thumb force to inject, and providing greater confidence in completing a full dose compared with usual PNs in this group of patients with type 1 or type 2 DM. ClinicalTrials.gov identifier: NCT01852136

Purpose The objective of this study was to compare the efficacy of peritonsillar and glossotonsillar sulcus infiltration with bupivacaine to manage postoperative pain and odynophagia in children undergoing tonsillectomy. Methods Fifty children (5–10 years of age) undergoing tonsillectomy due to recurrent tonsillar infections were enrolled in the study and assigned into two groups receiving either pre-incisional peritonsillar (Group 1, n  = 25) or glossotonsillar sulcus (Group 2, n  = 25) infiltration with 1 mg/kg bupivacaine (0.5%) totaling 5 mL in volume. At different time intervals following arrival to the post-anesthesia care unit (PACU), the participants in each group were evaluated for pain using the modified Children’s Hospital of Eastern Ontario Pain Scale (mCHEOPS) and for odynophagia using a four-point scale (1—none, normal or no difficulty with swallowing, 2—mild, mild difficulty with swallowing, 3—moderate, moderate difficulty with swallowing, and 4—severe, no swallowing or swallowing only with maximal effort). Additional parameters were assessed for 24 h post-surgery, including time to first administration of analgesic, additional analgesic requirements, nausea/vomiting, allergic reaction, and bleeding. Results Infiltration of either region with bupivacaine yielded similar analgesic effects at different times following the surgery ( P  = 0.065). Time to first analgesic treatment and additional analgesic requirements were not significantly different between groups ( P  = 0.181). Compared to the Group 1, Group 2 was associated with significantly lower odynophagia scores at different times after the surgery ( P  = 0.020). Conclusion Present results indicate that the infiltration of local anesthetics to glossotonsillar sulcus is a safe, practical, and effective pain management intervention without risk of significant side effects for children undergoing tonsillectomy.

Background: In randomized, controlled, double-blind, multicenter phase 3 studies, one icatibant injection was efficacious and generally well tolerated in patients with a single hereditary angioedema (HAE) attack. Here, the efficacy and safety of icatibant for multiple HAE attacks was evaluated across the controlled and open-label extension phases of the For Angioedema Subcutaneous Treatment (FAST)-3 study (NCT00912093). Methods: In the controlled phase, adults with HAE type I or II were randomized (1:1) to receive a single subcutaneous injection of icatibant 30 mg or placebo within 6 h of an attack becoming mild (laryngeal) or moderate (cutaneous/abdominal). Open-label icatibant was administered for severe laryngeal symptoms. In the open-label extension phase, patients could receive up to three icatibant injections per attack. Efficacy and safety were analyzed for the first five icatibant-treated attacks at any location (prospective analysis) and laryngeal attacks (post hoc analysis) across both phases. Efficacy outcomes were based on patient-reported symptom severity (visual analog scale). Results: In groups of patients with one to five icatibant-treated attacks at any location (n = 88), the median times to onset of symptom relief, onset of primary symptom relief and almost complete symptom relief were 1.9-2.1, 1.5-2.0 and 3.5-19.7 h, respectively. The same outcomes for laryngeal attacks (n = 25) were 1.0-2.0, 1.0-2.0 and 1.5-8.1 h, respectively. The most frequently reported adverse events were a worsening or recurrence of HAE attack, headache and nasopharyngitis. Two serious adverse events (arrhythmia and noncardiac chest pain) were considered to be related to icatibant. Conclusions: Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.

Purpose For patients with clinically significant risk of febrile neutropenia, pegfilgrastim administration should occur the day after myelosuppressive chemotherapy; however, a variety of factors may preclude patients from returning to the clinic the next day for pegfilgrastim administration, necessitating other strategies. This study compared the pharmacokinetics and safety of pegfilgrastim administered via an on-body injector applied to the subject’s skin versus manual injection using a prefilled syringe. Methods Healthy subjects aged 18–50 years were randomized 1:1 to receive a single 6-mg subcutaneous pegfilgrastim dose from an on-body injector or a prefilled syringe. Blood for pharmacokinetic measurements was collected at baseline and prespecified time points after pegfilgrastim administration; safety was assessed throughout the 6-week study. Primary endpoints were maximum concentration ( C max ) and area under the concentration curve from time 0 to infinity (AUC 0–inf ). Secondary endpoints included safety, tolerability, and immunogenicity. Results Pegfilgrastim mean AUC 0–inf values for the on-body injector ( n  = 125) and manual injection ( n  = 128) were 10,900 and 11,100 h ng/mL, respectively; mean C max values were 248 and 262 ng/mL, respectively. The least squares geometric mean ratios were 0.97 for C max and 1.00 for AUC 0–inf ; the corresponding 90 % CIs were within the prespecified range (0.80–1.25), indicating comparable pegfilgrastim pharmacokinetics between delivery methods. Treatment-emergent adverse events (AEs) were similar between groups (injector, 86 %; manual, 85 %). Injector- or syringe-related AEs were more prevalent with the injector (13 %; manual, 4 %); none were serious. No pegfilgrastim-neutralizing antibodies were detected. Conclusions Pegfilgrastim pharmacokinetics and safety were comparable between the on-body injector and manual injection groups.