Injection Site Induration Research Articles

Post-Marketing Surveillance of Adverse Events Following Immunization with Haemophilus Influenzae Type b Conjugate Vaccine - China, 2010-2021.

The Haemophilus influenzae type b (Hib) conjugate vaccine is widely administered in China. We extracted data on Hib vaccine doses administered and adverse events following immunization (AEFI) reported between 2010 and 2021 from the Chinese National Immunization Information System (CNIIS). A descriptive analysis was conducted to examine the characteristics and incidence rates of AEFI with the Hib vaccine. In China, between 2010 and 2021, a total of 52,910 AEFIs with the Hib vaccine were reported, resulting in an overall AEFI reporting rate of 38.10 per 100,000 doses. Common (typically minor) and rare (potentially serious) vaccine reactions occurred at rates of 34.71 and 2.78 per 100,000 doses, respectively. Among the common vaccine reactions, the incidences of fever (axillary temperature ≥38.6 ℃), injection site redness and swelling (>2.5 cm in diameter), and injection site induration (>2.5 cm in diameter) were 11.93, 9.69, and 3.38 per 100,000 doses, respectively. Rare vaccine reactions included anaphylactic rash, angioedema, and febrile convulsion with reported incidences of 2.42, 0.10, and 0.05 per 100,000 doses, respectively. The incidence of serious rare vaccine reactions was 0.16 per 100,000 doses. The reported incidence of AEFI with the Hib vaccine was low, with the occurrence of serious rare adverse reactions also being markedly low throughout the period 2010-2021 in China.

TAS0313 plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor-Naïve Locally Advanced or Metastatic Urothelial Carcinoma.

We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma (la/mUC). TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarkers of response were assessed. In 36 patients enrolled, the ORR was 33.3% (complete response: 7 patients; partial response: 5 patients). Median PFS was 5.0 months; 6- and 12-month progression-free rates were 46.4% and 36.5%, respectively. Median OS was not reached; 6-, 12-, and 24-month OS rates were 83.3%, 72.2%, and 55.1%, respectively. In post hoc analysis, patients with a tumor infiltrating CD8+ lymphocyte (CD8+ TIL) count ≥99 and/or programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥50 and lymphocyte count >1,380 cells/μL had higher ORRs and prolonged PFS versus patients with a CD8+ TIL count <99, PD-L1 CPS <50, and lymphocyte count ≤1,380 cells/μL. Thirty-four (94.4%) patients receiving combination therapy experienced treatment-related adverse events (AE), with pyrexia (n = 15, 41.7%), injection-site reactions (n = 15, 41.7%), injection-site induration (n = 6, 16.7%), and malaise (n = 6, 16.7%) the most common. No grade ≥3 treatment-related AEs occurred in ≥10% of patients. TAS0313 plus pembrolizumab combination therapy showed promising efficacy and manageable safety in la/mUC. Clinical Trial Registration: JapicCTI-183824.

KP104, a Bifunctional C5 Antibody/Factor H Fusion Protein, Effectively Controls Both Intravascular and Extravascular Hemolysis: Interim Results from a Phase 2 Study in Complement Inhibitor-Naïve PNH Patients

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disease characterized by intravascular and extravascular hemolysis (IVH and EVH) mediated by complement activation through both the terminal and alternative pathways (TP and AP). The current treatment options for PNH are limited to addressing only a single complement pathway, resulting in either unresolved EVH with TP inhibitors or potentially exposing patients to the risk of life-threatening breakthrough hemolysis with AP inhibitors (Notaro et al. N Engl J Med 2022;387:160-6). KP104 is an innovative fusion protein comprised of a humanized anti-C5 mAb and the functional domain of complement regulator factor H to inhibit both TP and AP activation. We report here the interim results from a phase 2 study of KP104 in complement inhibitor-naïve PNH patients. Methods This open-label Phase 2 clinical trial (NCT05476887) aims to assess the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KP104 in patients diagnosed with PNH who have not received prior complement inhibitors. The primary objectives of the study are to evaluate key clinical markers including lactate dehydrogenase (LDH) and hemoglobin (Hgb) levels, transfusion requirements, and FACIT-fatigue scores. The first part of the study consists of three cohorts, with an enrollment of 6 patients per cohort. The study includes an initial treatment period of 12 or 13 weeks of KP104 dosing regimen, followed by a 9-month extension treatment period. The specific dosing regimens for each cohort are as follows: Cohort 1: 1,200 mg IV (Day 1) + 720 mg SC QW (starting Day 8) Cohort 2: 2,400 mg IV (Day 1) + 1,920 mg SC Q2W (starting Day 8) Cohort 3: 3,600 mg IV (Day 1) + 2,880 mg SC Q2W (starting Day 8) Results Interim results include data from 15 patients who completed 16/17 weeks of treatment (6 patients each from Cohort 1 and 2, and 3 from Cohort 3), as of the data cutoff on July 12 th, 2023. Among these patients (4 males and 11 females, mean (±SD) age 33(±12) years, a median of 3 transfusions were required 12 months prior to the study and 9 patients were previously diagnosed with aplastic anemia. Baseline mean (SD) Hgb and LDH levels were 7.0 (±1.5) g/dL and 1,824 (±512) U/L, respectively. By week 16/17, all 15 patients demonstrated positive clinical improvements. Mean (SD) Hgb levels increased by 4.9 (±1.7) g/dL, 5.8 (±1.6) g/dL, and 5.8 (±2.8) g/dL over baseline, and mean (SD) LDH levels reduced by 88.0 (±3.67) %, 83.5 (±7.45) %, and 89.5 (±4.05) % over baseline for Cohort 1, 2 and 3, respectively. Additionally, 9/15 (60%) patients achieved hemoglobin levels ≥12 g/dL (3/6, 5/6 and 1/3 for Cohort 1, 2 and 3, respectively), and all 15 patients had LDH levels below 1.5xULN. None of the 15 patients required transfusions or encountered any thromboembolic events after receiving KP104 treatment. Positive changes were observed in absolute reticulocyte count and bilirubin levels, along with significant enhancements in FACIT-fatigue scores seen in all 3 cohorts, with mean (SD) increases of 13.8 (±7.91), 12.8 (±9.15), and 9.3 (±10.69) for Cohorts 1, 2, and 3, respectively. Dose-dependent reductions in two PD biomarkers, C3b deposition and free C5 levels, further confirmed KP104's dual mechanism of AP and TP inhibition. KP104 was well tolerated, with no serious adverse events or treatment-emergent adverse events (TEAEs) that led to drug discontinuation or study withdrawal. 10/15 (67%) patients reported at least one mild or moderate TEAE, with no observed dose dependency. The most frequently reported TEAEs included transient injection site induration, headache, and COVID-19 infection, all of which were promptly or duly resolved. A single occurrence of clinical breakthrough hemolysis, observed in the lowest dose cohort and concurrent with an episode of gastroenteritis, was quickly resolved after an extra dose. Conclusion The interim results of this phase 2 study demonstrate the safety and efficacy of KP104 in effectively controlling IVH and EVH in complement inhibitor-naïve PNH patients. The findings provide compelling clinical evidence that a bifunctional inhibitor targeting the AP and TP can properly address the current treatment gaps associated with single complement pathway inhibitors, potentially eliminating the need for cumbersome and costly combination therapies (Notaro et al. N Engl J Med 2022;387:160-6).

Patient satisfaction of microfocused ultrasound treatments on the face and neck laxity: A narrative review.

Microfocused ultrasound with visualization (MFU-V) delivers focused ultrasound energy to heat tissue and has emerged as a fast and effective noninvasive method for treating skin laxity. After obtaining approval in 2009 by the Food and Drug Administration, satisfactory feedback was recorded using several scoring systems for MFU-V treatment for facial and neck laxity. To evaluate the efficacy and satisfaction rates of MFU-V for facial and neck laxity treatment by providing a basis for developing a validated scoring system for MFU-V treatment. A constrictive survey was carried out by selecting relevant publications on MFU-V treatment of facial and neck laxity using PubMed, Medline, and Embase electronic databases from January 2017 to March 2022. Of the 11 original articles used in this review, the majority of the scoring methods used were the subjective global aesthetic improvement scale and the 5-point scale rating global aesthetic improvement in appearance. Around half of the patients were described as much improved or very much improved on days 30 and 90, while most returned to baseline on Day 360. Most of the adverse events reported were mild bruising, redness, and pain. None of the patients reported serious adverse events. A burn occurred in one case because of improper application of the probe. The MFU-V provides excellent and promising responses for treating facial and neck laxity. A few mild events were observed, such as erythema, pain, edema, and injection-site induration, all of which resolved within approximately 2-3 days.

Subcutaneous (SC) isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM): Interim phase 1b study results.

8025 Background: Intravenous (IV) isatuximab (Isa) + Pd is approved for the treatment of RRMM patients (pts). SC delivery would optimize convenience of administration. Prior results showed that SC Isa administered by syringe pump has efficacy and safety profiles comparable to IV Isa; the recommended Phase 2 dose (RP2D) was 1400 mg (IMW21 P-207). Methods: This multicenter Phase 1b study evaluated safety, PK and efficacy of SC vs IV Isa + Pd in RRMM pts after ≥2 prior treatment lines. Pts were randomized 2:1 to SC1000 mg or IV 10 mg/kg and to SC1400 mg or IV. An expansion cohort was later implemented with SC Isa administered at the RP2D via OBDS, a wearable bolus injector applied to the abdomen by a healthcare professional. Primary endpoints (EPs) were safety, including injection site reactions (ISRs), and PK. Main secondary EPs were overall response rate (ORR) and progression-free survival (PFS). Results: 56 pts were randomized and treated: 12 Isa IV, 12 Isa SC1000, 10 Isa SC1400 and 22 OBDS pts. At study entry, ISS stage II–III was 67% in IV, 33% in SC1000, 60% in SC1400 and 50% in OBDS pts. On Jan 20, 2022, 33% IV, 25% SC1000, 50% SC1400 and 86% OBDS pts remained on treatment. Due to sequential accrual, median follow-up (FU) was longer in IV (20.6 mo) and SC1000 (23.8 mo) than SC1400 (18.1 mo) and OBDS (6.5 mo) pts. Infusion reactions (IRs) were infrequent (≤10% in each cohort, all Grade [G] 2), only at first IV or SC infusion/injection, with no IRs in OBDS. Local tolerability of OBDS was very good, with 5 (22.7%) pts experiencing 7 ISR episodes, all G1, out of 305 administrations (2.3%): 5 injection site erythemas, 1 injection site hemorrhage, and 1 injection site induration. Median duration of OBDS injection was 10 min. Incidence of G4 neutropenia was lower in SC1000 (42%) vs the other cohorts (55–60%). The lower % of ≥G3 treatment-related AEs in OBDS (77%) vs the other cohorts (≥80%) may be due to shorter FU. Best overall responses are shown in table; longer FU is needed for OBDS pts. Median PFS was 22 mo in IV, 12.5 mo in SC1000 and not reached in SC1400 and OBDS pts. PK and CD38 receptor occupancy results in OBDS pts are consistent with those observed in SC1400 with pump. Conclusions: SC Isa administered by OBDS shows a safety profile consistent with IV administration with no IRs and excellent local tolerability. Efficacy in the SC cohorts was comparable to the Phase 3 ICARIA results. Isa SC administration by OBDS is well tolerated, requires a short duration of injection and provides a convenient hands-free option. Clinical trial information: NCT04045795. [Table: see text]

Surveillance of adverse events following the introduction of inactivated poliovirus vaccine made from Sabin strains (sIPV) to the Chinese EPI and a comparison with adverse events following inactivated poliovirus vaccine made from wild strains (wIPV) in Jiangsu, China

ABSTRACT One dose of inactivated poliovirus vaccine (IPV) was introduced into the Chinese Expanded Program on Immunization (EPI) in 2016. IPV made from Sabin strains (sIPV) was newly licensed in China and its safety has been concerned. This study aimed to evaluate the safety of sIPV and provide a comparison with conventional IPV made from wild strains (wIPV). We collected all IPV-related AEFI reports in Jiangsu from the Chinese National Adverse Events Following Immunization Information System (CNAEFIS) for 2016–2019. We obtained the administered doses of IPV from the Jiangsu provincial Electronic Immunization Registries System (JSEIRS). The AEFI reporting rates per 100,000 doses of vaccine administered were compared for sIPV and wIPV. A total of 699 sIPV and 908 wIPV AEFI cases were collected by CNAEFIS in Jiangsu during 2016–2019. The overall AEFI reporting rates were 53.02 per 100,000 doses and 41.25 per 100,000 doses for sIPV and wIPV, respectively (P < .001). For both sIPV and wIPV, the AEFIs were mainly classified as common adverse reactions. The reporting rate of common adverse reactions was higher for sIPV than for wIPV (P < .001). The most frequently reported symptoms/signs were fever, persistent crying, injection site erythema/swelling, rash, and injection site induration. Only 1.14% of sIPV-associated and 2.31% of wIPV-associated AEFI cases were diagnosed as serious. No difference in reporting rate was observed for serious AEFIs (P = .272). sIPV has a favorable safety profile, although it exhibits a slightly higher reporting rate of common adverse reactions than wIPV.

Immunogenicity and safety of a novel ten-valent pneumococcal conjugate vaccine in healthy infants in The Gambia: a phase 3, randomised, double-blind, non-inferiority trial

Immunogenicity and safety of a novel ten-valent pneumococcal conjugate vaccine in healthy infants in The Gambia: a phase 3, randomised, double-blind, non-inferiority trial

SUN-094 Long-Term Safety and Efficacy of Leuprorelin in Treating Central Precocious Puberty: A Large, Open-Label, Multicenter, Phase IV Study in China

BACKGROUND: Leuprorelin (Enantone®) is a gonadotropin-releasing hormone (GnRH) analogue used worldwide to treat central precocious puberty (CPP). This clinical trial aimed to evaluate the long-term safety and efficacy of leuprorelin in treating Chinese CPP children. Methods: This is the first, prospective, open-label, and multicenter study conducted from 2015 to 2018, in China. As a large interventional study, it included a four-week screening period, a 96-week treatment period, and a four-week safety follow-up period. Eligible subjects were treated with leuprorelin subcutaneously once every four weeks for 96 weeks. At the beginning of the study, subjects whose body weight ≥20 kg received a dose of 3.75 mg and those <20 kg received a dose of 1.88 mg and then the dose was allowed to be adjusted during the study based on subject’s condition and investigator’s judgment. The primary endpoint was the incidence of adverse events during treatment, and the secondary endpoint was the percentage of subjects who had regression or no progression in Tanner stage at Week 96 compared with baseline. Results: A total of 307 CPP patients from 11 Chinese medical centers received leuprorelin, of which 305 (99.3%) were girls and 2 were boys (0.7%), with a mean (±SD) age of 7.95±0.982 years and a mean height of 133.68±7.108 cm. Two hundred eighty-three (92.2%) patients completed the 96-week treatment period. Two hundred fifty-two patients (82.1%) reported treatment-emergent adverse events (TEAEs)—most of which (79.5%) were mild to moderate. Only 33 (10.7%) patients experienced TEAEs that were considered related to leuprorelin. The most frequent (>2%) drug-related TEAEs were injection site induration (4.6%, 14/307) and vaginal bleeding (2.3%, 7/305). After the 96-week treatment period, 83.5% female subjects had regression or no progression in Tanner stage compared with baseline (95% CI: 78.68%, 87.62%) and the 2 male subjects had progression of 1 point in Tanner stage genital score occurred at Week 12 and then remained stable throughout the study. By the end of the treatment period, the majority of subjects had decreased GnRH stimulated peak LH and FSH, as well as reduced sex hormone levels and bone age/chronological age ratio compared with baseline. The subjects also had increased predicted adult height and BMI after treatment. Conclusions: This Chinese study demonstrated that CPP was effectively treated in most patients who received leuprorelin (Enantone®) for nearly two years. Any drug-related adverse events were reported with low incidence (<5%) and were consistent with the known safety profile of leuprorelin. Leuprorelin was shown to be well tolerated and effective in the management of CPP in Chinese patients.

Long-term safety and efficacy of lanreotide treatment in Japanese patients with neuroendocrine tumors: Final analysis of a phase II open-label extension study.

621 Background: Lanreotide autogel 120mg (lanreotide) was approved in Japan in July 2017 for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs) based on the results from an international phase III study (CLARINET study) and a Japanese single-arm phase II study. The CLARINET extension study demonstrated long-term efficacy and safety of lanreotide treatment; however, no Japanese patients were included in the study. To describe the safety and efficacy of long-term lanreotide treatment for NETs in Japanese patients, the final analysis of the Japanese phase II study and its extension study was performed. Methods: This open-label extension study (Study 002, JapicCTI-142698) enrolled patients who completed 48 weeks of treatment with 4-weekly subcutaneous lanreotide in an open-label phase II study in Japanese patients with NETs (Study 001, JapicCTI-132375). Study 002 had the same design as Study 001. Results: Of the 32 patients who started treatment with lanreotide, 17 completed Study 001 and enrolled in Study 002. In the safety analysis set (n = 17), 16 patients (94.1%) developed adverse events (AEs) that were considered drug-related (adverse drug reactions; ADRs), most commonly faeces pale (n = 5; 29.4%), injection site induration (n = 4; 23.5%), flatulence and diabetes mellitus (both n = 3; 17.6% each). No patient permanently discontinued lanreotide or died as a result of an AE. Four patients had a total of eight serious AEs; of these, two events of bile duct stones were considered to be ADRs. In the efficacy analysis set (n = 28), the median lanreotide exposure over Studies 001 and 002 was 52.7 weeks (range: 12–181 weeks). The best overall response was partial response in 2 patients (7.1%; reached at 60 and 108 weeks), stable disease in 20 patients (71.4%) and progressive disease in 6 patients (21.4%). Conclusions: No unexpected serious AEs developed during prolonged use of lanreotide. Lanreotide was effective over long-term treatment in Japanese patients with NETs. Clinical trial information: JapicCTI-132375, JapicCTI-142698.

Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine

Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose. Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95% CI, -2.01 to -0.93 days; P < .001) and with single higher dosing vs placebo of -1.3 days (95% CI, -1.79 to -0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy. clinicaltrials.gov Identifier: NCT02629861.

Phase II study of lanreotide autogel in Japanese patients with unresectable or metastatic well-differentiated neuroendocrine tumors

SummaryBackground Lanreotide is a long-acting somatostatin analog with demonstrated efficacy against enteropancreatic neuroendocrine tumor (NET) in the phase III (CLARINET) study. Materials and Methods In this single-arm study, Japanese patients with grade (G) 1/G2 NET received lanreotide (120 mg/4 weeks) for 48 weeks. Those who completed the study were enrolled in a long-term extension study. The primary endpoint was the clinical benefit rate (CBR) defined as a complete response, partial response (PR), or stable disease (SD) over 24-weeks. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and pharmacokinetics. Results Thirty-two patients were recruited at 10 sites. The full analysis set (FAS) comprised 28 patients. Primary tumors were located in pancreas (12 patients), foregut (non-pancreas, lung; 1), midgut (2), hindgut (8), and unknown (5). Four patients had gastrinoma of the functional NET, and 3 had multiple endocrine neoplasia type 1. In the FAS, 39.3% had progressive disease at baseline. The CBR at 24 weeks was 64.3% (95% confidence interval; CI: 44.1–81.4), and median PFS was 36.3 weeks (95% CI: 24.1–53.1). PR was confirmed in 1 patient at 60 weeks during the extension study (ORR: 3.6%). Frequent adverse events related to lanreotide included injection site induration (28.1%), faeces pale (18.8%), flatulence (12.5%), and diabetes mellitus (12.5%). Conclusions The efficacy and safety of lanreotide in this study indicated its usefulness as a treatment option for Japanese NET patients. Trial registration: JapicCTI-132,375, JapicCTI-142,698.

An open-label, single-group, multicenter phase II study of lanreotide autogel (LAN) in Japanese patients (pts) with neuroendocrine tumors (NET).

471 Background: LAN is a long-acting somatostatin analog indicated in EU for the treatment of carcinoid syndrome and in the US and EU as antiproliferative treatment in pts with gastroenteropancreatic (GEP) -NET. The antitumor efficacy of LAN in pts with GEP-NET was evaluated in the phase III CLARINET study. No study to date has reported the antitumor effects of somatostatin analog in Japanese pts with NET. Methods: In this open-label, single-arm study, Japanese pts with Grade 1 or 2 unresectable metastatic or locally advanced NET received 120 mg once every 4 weeks for 48 weeks. Pts who completed the study were subsequently enrolled in the long-term extension study. The primary endpoint was the clinical benefit rate (CBR: the ratio of pts with a complete response, a partial response (PR), or stable disease over 24 weeks). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) (RECIST 1.1, central review), serum chromogranin A (CgA) level and quality of life using the EORTC QLQ-C30. The results of the CLARINET study cohort were compared with those from a matched population. Results: 32 pts were recruited in 10 sites. Mean age was 61.7 years. 67.9% were male. The primary tumor sites were pancreas (n = 14), foregut (2), midgut (2), hindgut (8), and unknown (6). Four pts had gastrinoma, and 3 of them had multiple endocrine neoplasia type 1. In the Full Analysis Set (n = 28), 39.3% of pts had progressive disease at baseline according to RECIST criteria. The CBR at 24 weeks was 64.3% (18 of 28 pts) and the median PFS was 36.3 weeks. A PR was confirmed in 1 patient during the 60 weeks of the extension study (ORR: 3.6%). For PFS, the subgroup analysis showed that the results of pts with no progressive disease at baseline or prior treatments for NET were similar to the results of pts in the CLARINET study. LAN decreased serum CgA by at least 50% in 15 of 17 pts (88.2%) who had elevated CgA levels at baseline. Frequent adverse reactions included injection site induration (28.1%), pale stools (18.8%), flatulence (12.5%), and diabetes (12.5%). Conclusions: The efficacy and safety of LAN in this study clearly show that LAN will be a useful treatment option for Japanese pts with NET. Clinical trial information: 132375,142698.

Safety of ASP0113, a cytomegalovirus DNA vaccine, in recipients undergoing allogeneic hematopoietic cell transplantation: an open-label phase 2 trial

Cytomegalovirus (CMV) infection/reactivation is a serious complication after hematopoietic cell transplantation (HCT). The DNA vaccine ASP0113 contains two plasmids encoding CMV antigens (glycoprotein B and tegument phosphoprotein 65) that stimulate humoral and cellular immunity. Between June 2013 and February 2014, Astellas conducted a phase 2, open-label, uncontrolled, three-center trial to investigate the safety and tolerability of ASP0113 in Japanese patients undergoing HCT for hematologic disorders. Ten patients aged 22-61years were enrolled; nine received at least one dose of ASP0113. Six patients received all five doses of ASP0113 5mg at intervals before and after HCT. Pre-emptive antiviral therapy was allowed. One patient died following relapse of primary disease. All patients had serious adverse events deemed unrelated to ASP0113. CMV viremia (assessed by CMV antigenemia) occurred in seven patients, who then received anti-CMV therapy. No patients developed CMV end-organ disease. Adverse events associated with ASP0113 injection included pyrexia (three patients), skin reactions [injection site pain, injection site tenderness, and erythema (two patients each); and rash, injection site erythema, injection site induration, and injection site swelling (one patient each)], and hyperuricemia (one patient). ASP0113 was well tolerated in Japanese HCT recipients. Further studies should evaluate its efficacy and safety. ClinicalTrials.gov Identifier: NCT01903928.

Evaluation of Tuberculin Skin Test (TST) in Medical Students in Mazandaran University of Medical Sciences, Sari, Iran

&lt;p&gt;&lt;strong&gt;BACKGROUND: &lt;/strong&gt;Working in health care units has been known as occupational risk factor in mycobacterium tuberculosis (TB) infection. The TB exposure rate in medical students is more than other people. In several studies significant correlation has been reported between hospital presence hours and positive PPD test prevalence. With regard to morbidity of several medical students and nursing staff due to primary tuberculosis in recent years, we decided to investigate positive tuberculin skin test (TST) prevalence in medical students and examine correlation between positive cases prevalence with presence hours in hospitals.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;METHODS: &lt;/strong&gt;This was a cross sectional study and 297 medical students of Mazandaran University of medical sciences were investigated. TST was done with Mantoux method. After 48 hours, injection site induration was measured. Subjects that had induration &amp;lt;10 millimeters were injected again (1-3 weeks later) with same method. (As a booster dose)&lt;/p&gt;&lt;p&gt;&lt;strong&gt;RESULTS: &lt;/strong&gt;32 cases (10.7%) had positive test at the first phase. Second phase was done on rest 265 persons and 20 cases had positive test. In summation 52 positive cases (17.5%) were observed. 21 cases of 151 persons (13.9%) in group with &amp;lt;100 hours/annual hospital presence, had positive tests. 21 cases of 71 persons (16.9%) in group with 100-1000 h/a hospital presence (Extern) and 19 cases of 75 people (25.3%) those who had &amp;gt;1000 h/a hospital presence(Intern), had positive tests. There was a meaningful statically difference in positive tests, between groups &amp;lt; 1000 hours exposure and the other who had &amp;gt; 1000 hours contact (p=0.032).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;CONCLUSIONS: &lt;/strong&gt;Because of, Interns’ high responsibilities and their more involvement in patient’s diagnostic and therapeutic process, they have high chance to contact with undiagnosed and diagnosed tuberculosis patients. Due to these reasons, TB infection rate is increasing among Interns. As a result of these findings, performing PPD test should be considered at the beginning of entrance to hospital departments and then annually. Necessary tasks and following up are needed to new positive cases.&lt;/p&gt;

Safety of the Northern Hemisphere 2014/2015 formulation of the inactivated split-virion intramuscular trivalent influenza vaccine

In the current study, the safety of the 2014/2015 Northern Hemisphere formulation of Vaxigrip® (Sanofi Pasteur) was assessed to satisfy European Union requirements. Individuals ⩾6months of age eligible for seasonal influenza vaccination were included. Children 6months–8years of age received one dose (0.25ml for 6–35 mo; 0.5ml for 3–8y) on day 0, and those who were previously unvaccinated received a second dose of the same volume on day 28. Participants ⩾9years of age received one full dose (0.5ml) on day 0. Frequency categories for solicited reactions were compared with historical data for the closest age group available. A total of 527 participants were included (6mo–5y, n=106; 6–12 y, n=105; 13–17 y, n=106; 18–65 y, n=105; >65 y, n=105). Frequency categories were higher in this study than for the historical comparator for fever (very common vs. common) in participants 6months–5years of age; shivering (very common vs. common), rash (uncommon vs. very rare), and grade 3 injection-site induration (common vs. uncommon) in participants 6–12years of age; and shivering in participants 13–17years of age (very common vs. common) and >65years of age (very common vs. common). However, these increases were not considered clinically significant because confidence intervals for proportions were overlapping and because most of the reactions were of grade 1 to 2 and resolved rapidly and spontaneously. No treatment-related serious adverse events were recorded and no safety concerns or safety signals were detected. These results indicate that the 2014/2015 Northern Hemisphere formulation of Vaxigrip was well tolerated and safe to use in all age groups, with no specific concerns identified, although the study was not powered to detect rare or very rare events.

Advances in anti-IgE therapy.

Omalizumab depletes free IgE in the blood and interstitial space and inhibits IgE binding to FcεRI on basophils, mast cells, and dendritic cells. We stopped omalizumab treatment after four years. Recurrences of urticaria symptoms were found to be higher in patients with chronic urticaria than recurrences of asthmatic symptoms in severe persistent asthma patients. For the very first time, we used omalizumab in symptomatic therapy of recurrent laryngeal oedema and urticaria attacks in a patient with postoperative pulmonary carcinoid tumor for eight months. During the four years of follow-up, no recurrence was noted in pulmonary carcinoid tumor. Control PET CT results revealed normal findings. After omalizumab treatment, laryngeal oedema and urticaria symptoms were decreased. The most common adverse reaction from omalizumab is injection site induration, injection site itching, injection site pain, and bruising but the package insert contains warnings regarding parasitic infections. While there are no reports of fatal anaphylaxis as a result of omalizumab, some cases have been serious and potentially life-threatening. Therefore, the FDA requires that people receiving omalizumab be monitored in the physician's office for a period of time after their injections.

Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-Vs.-Host Disease: Phase 2 and Long Term Efficacy, Safety and Immune Correlates

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) results from incomplete reconstitution of immune tolerance. CD4+CD25+FOXP3+ regulatory T cells (Treg) are required for tolerance and function as dominant suppressors of innate and adaptive immune effector cells. In our prior phase 1 cGVHD study daily subcutaneous (SC) low-dose interleukin-2 (IL-2) for 8 weeks induced Treg expansion in vivo and objective clinical responses in 12 of 23 evaluable participants (NEJM 2011). We now report on a phase 2 trial of daily low-dose SC IL-2 at 1x106 IU/m2/d for 12 weeks in steroid-refractory cGVHD.The study comprised 35 HCT recipients (51% male, 91% HLA-matched PBSC grafts). Median participant age was 51 years (range, 22-72). Median time from HCT and from cGVHD onset to start of IL-2 treatment was 616 days (range, 270-2145) and 252 days (range, 28-1880) respectively. Participants had a median of 4 cGVHD organ sites (range, 1-7), and 2 concurrent cGVHD therapies (range, 1-3) at enrollment. The median baseline prednisone dose was 20 mg (range, 2.5-50). The median follow-up in survivors was 21 months (range, 4-35).12 week low dose IL-2 was well tolerated: 2 participants withdrew and 5 required IL-2 dose reduction for constitutional AE (n=6) and thrombocytopenia (n=1); 1 had Gr 3 infection (bacteremia); and none experienced relapse. At week 12, objective cGVHD responses (PR) were documented in 21 of 33 evaluable participants (64%). Two (6%) had cGVHD progression. cGVHD response sites included skin (n=9), joint/fascia/muscle (n=4), liver (n=7), lung (n=3), and GI tract (n=4). Overall 2-year OS/PFS was 91% (responders 94%; non-responders 83%). 23 participants with clinical benefit (PR or SD with minor response) proceeded on extended IL-2 therapy.Immunologically, low dose IL-2 induced a >4-fold increase in median Treg count/µL (p<0.001): a rapid rise from a baseline of 17.1 (Q1-Q3, 8.6-40.6) to a week 4 peak of 137.9 (Q1-Q3, 51.8-188) and subsequent stabilization with a week 12 count of 104.1 (Q1-Q3, 53.9-167.1). No significant change in CD4 conventional T cell (Tcon), CD8 T cell, or CD20 B cell count was noted. NK cell count increased >3-fold (p<0.001). The median Treg:Tcon ratio increased >4-fold (p<0.001): a rapid rise from baseline of 0.06 (Q1-Q3, 0.05-0.13) to a week 2 peak of 0.35 (Q1-Q3, 0.26-0.48) that remained elevated through a week 12 ratio of 0.31 (Q1-Q3, 0.27-0.39) (Figure). Treg count and Treg:Tcon ratio declined during 4 weeks off IL-2 and rose thereafter on restarting IL-2.Clinical responders were younger (50 vs. 61.5 years, p=0.01) and initiated IL-2 earlier (499 vs. 903 days post HCT, p=0.015). Responders had a higher median Treg:Tcon ratio at study baseline (0.09 vs. 0.06, p=0.052) and at week 1 of IL-2 (0.3 vs. 0.14, p=0.01). Combining phase 1 and 2 data, Treg:Tcon ratios of ≥0.07 at baseline and ≥0.2 at week 1 of IL-2 were highly predictive of clinical response (p=0.007; p=0.0013 respectively).The combined phase 1 and 2 extended IL-2 cohort comprised 35 participants with a median follow up of 16.2 months (range, 4.1-66.8), with 20 and 12 participants receiving over 1 and 2 years of IL-2 respectively. Extended daily low dose IL-2 was well tolerated, and only 4 participants had Gr 3 AEs deemed IL-2 related: lung infection (n=1), arthralgia (n=1), and injection site induration (n=2). 5 participants required IL-2 dose reduction and 1 had hematologic malignancy relapse. Clinical responses were typically sustained during taper of concomitant immunosuppression. Treg augmentation persisted for the duration of IL-2 therapy. Tcon count slowly recovered to normal levels and Treg:Tcon ratio gradually normalized over a 2 year period. There was no change in CD8 count. The median steroid taper was 50% (range, -20-100).In summary, daily low dose IL-2 therapy induced profound Treg enhancement, and clinical responses in over half of refractory cGVHD patients. Early clinical response predictors suggest IL-2 is more effective earlier in the cGVHD course and when starting numbers of Treg are higher. Sustained clinical and immunologic response during extended IL-2 was documented. Long term tolerance induction with daily low dose IL-2 is a promising and feasible strategy. Optimizing IL-2 clinical response by further augmenting Treg and the Treg;Tcon ratio early in the course of cGVHD is worth exploring. [Display omitted] DisclosuresKoreth:Prometheus Laboratories Inc: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Takeda Pharmaceuticals Inc: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Low-dose Interleukin-2 for immune tolerance. Chen:Bayer Pharmaceuticals, Inc.: Other, Research Funding. Avigan:Astex Pharmaceuticals : Research Funding.

Pharmacokinetic Properties and Effects of PT302 After Repeated Oral Glucose Loading Tests in a Dose-Escalating Study

BackgroundPT302 is a sustained-release exenatide under clinical development for the treatment of type 2 diabetes mellitus. ObjectiveThe aim of this study was to evaluate the pharmacokinetic properties, pharmacodynamic properties, and tolerability of PT302 after a single subcutaneous injection in healthy individuals. MethodsA dose-block randomized, double-blind, placebo-controlled, dose-escalating study (0.5, 1, 2, and 4 mg) was performed in 34 healthy individuals. The plasma concentrations of exenatide in serial blood samples were quantified for 56 days after dosing with an exendin-4 fluorescent immunoassay kit. Noncompartmental analysis was performed to assess the pharmacokinetic characteristics of PT302. Oral glucose tolerance tests were repeated weekly until day 42; the concentrations of serum glucose, serum C-peptide, plasma insulin, and plasma glucagon were measured for 2 hours to evaluate the pharmacodynamic characteristics of PT302. Clinical laboratory tests, vital signs, physical examinations, 12-lead ECGs, and adverse events were monitored to evaluate the safety profile and tolerability. ResultsPT302 exhibits a biphasic pharmacokinetic profile, with the initial peak occurring 2 hours after administration. PT302 was quantifiable in the plasma until days 23, 30, 32, and 55 (median) in the 0.5-mg, 1-mg, 2-mg, and 4-mg dosage groups of PT302, respectively. Systemic exposure increased proportionally to the dose during the entire dose range investigated. The pharmacodynamic effect of PT302 on the postprandial response of insulin and C-peptide was significant on days 21 to 28 at the 4-mg dose and was positively correlated with plasma exenatide concentrations, whereas the correlations with glucose and glucagon were not significant. The fasting levels of these pharmacodynamic biomarkers were not altered by PT302. The most common adverse events were injection site induration and pruritus related to inflammatory foreign body reaction, which were mild and spontaneously resolved within several weeks. ConclusionThe pharmacokinetic characteristics of PT302 were biphasic and dose proportional. A single 4-mg dose of PT302 significantly increased the insulin and C-peptide response to oral glucose loading and was well tolerated in healthy individuals. ClinicalTrials.gov identifier: NCT00964262.

Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

Efficacy and safety of exenatide once-weekly vs exenatide twice-daily in Asian patients with type 2 diabetes mellitus.

To compare safety and efficacy of the extended-release formulation exenatide once weekly (EQW) vs exenatide twice daily (EBID) for 26weeks in type 2 diabetes patients from China, India, Japan, South Korea and Taiwan. A randomized, comparator-controlled, open-label study included 681 patients with type 2 diabetes inadequately controlled (hemoglobin A1c [HbA1c] ≥7 and ≤11%) with oral antihyperglycemic medications (OAMs). Patients added 2mg EQW or 10μg EBID to current OAMs. Safety was re-evaluated 10weeks after last treatment. EQW was superior to EBID on HbA1c measures at week 26 (Least-squares mean treatment difference: -0.31% [95% confidence interval -0.49, -0.14%]). More EQW-treated patients achieved target HbA1c ≤7.0% (P=0.003), ≤6.5% (P<0.001), or ≤6.0% (P=0.003). Fasting serum glucose reductions were greater among EQW-treated patients (P<0.001). Bloodglucose profiles improved in both treatment groups (P<0.001). Weight loss occurred with both treatments, but was greater with EBID. Adverse events (≥10%, either group) were nausea, injection-site induration, dyslipidemia and vomiting. Injection-site induration was more frequent with EQW, whereas nausea, vomiting and hypoglycemia were less frequent. One episode each of major hypoglycemia (EBID) and pancreatitis (EQW) were reported. In this population, EQW and EBID showed efficacious glucose and weight control; safety and tolerability were consistent with observations in non-Asian patients. This trial was registered with ClinicalTrials.gov (no. NCT00917267).