Prevention of nodules and enhancement of antibody response to genetically engineered recombinant vaccine against Human Chorionic Gonadotropin (hCG) for contraception.

OBJECTIVE: Human Chorionic Gonadotropin (hCG) plays a crucial role in embryo implantation and in maintenance of pregnancy. An immuno-contraceptive approach involves the use of a recombinant hCGß-LTB vaccine formulated with adjuvant Mycobacterium indicus pranii (MIP), to prevent pregnancy without disturbing ovulation, hormonal profiles, and menstrual cycles in women. The present work in mice was designed to address issues encountered in clinical trials conducted with hCGß-LTB vaccine, with focus on two primary concerns. Firstly, it aimed to determine the optimal vaccine dosage required to induce a high level of anti-hCG antibodies. Secondly, it aimed to assess the safety profile of the vaccine, specifically injection site reactions in the form of nodules, observed in some of the subjects. METHODS AND RESULTS: Studies undertaken indicate that a 2 µg dose of the protein version of the vaccine, administered in mice through the intramuscular route, can induce high anti-hCG titres. Furthermore, administering a booster dose enhances the antibody response. Our findings suggest that the concentration and frequency of administration of the adjuvant MIP can also be reduced without compromising vaccine efficacy. CONCLUSION: The issue of nodule formation at the injection site can be mitigated either by administering the vaccine along with MIP intramuscularly or injecting hCG vaccine and MIP at separate intradermal sites. Thus, protein vaccine administered at a 2µg dose via the intramuscular route addresses both efficacy and safety concerns.

The Phase I/II clinical trials initiated with the recombinant hCG vaccine in women revealed inadequate antibody titres in all subjects, alongside the development of nodules at the injection sites in some participants. Studies were undertaken in mice to propose potential strategies for mitigating injection site reactions and enhancing the antibody response. It was concluded that the optimum dose of the protein version of the vaccine to get high antibody titres, is 2 µg administered intramuscularly while upholding safety standards.

Mycobacterium welchii Vaccine Granuloma - A Cautionary Tale.

BACKGROUND: Mycobacterium welchii (Mycobacterium w) vaccine was one of the many strategies used to both treat and prevent coronavirus disease 2019 (COVID-19) infection. We report the results of a retrospective analysis of 15 cases with vaccine-site granulomas after administration of prophylactic Mycobacterium w vaccine as part of a trial for COVID-19 and our experience in managing those cases. METHODS: This was a retrospective analysis of 15 patients with vaccine-site granulomas who were given the vaccine as a prophylactic measure as part of a trial with informed consent. RESULTS: The mean average age of cases was 37 and the male-to-female ratio was 1:0.87. All of the patients developed erythematous tender nodules over the injection sites within a month of receiving the inoculations. Mycobacterial cultures and cartridge-based nucleic acid amplification tests yielded negative results. Skin biopsy revealed granulomatous dermatitis with acid-fast bacilli positivity. A diagnosis of noninfective granulomatous dermatitis was made. Treatment started with analgesics and anti-inflammatory agents. Systemic antibiotics were required in 9/15 patients. Patients are being followed up with no reported recurrence till date. CONCLUSION: The possibility of injection-site granuloma should be taken into the risk-benefit analysis for the administration of Mycobacterium w vaccine and the patients should be counseled as such. Patients with persistent ulceration respond to combinations of doxycycline, ofloxacin, and clarithromycin.

One-Year Safety Evaluation of New Hyaluronic Acid Fillers (YYS Series): A Prospective, Multicenter, Observational Study.

BACKGROUND: With the continuous increasing availability of new filler products, each hyaluronic acid filler brand has distinctive pharmacokinetics, which may be associated with different complications. Therefore, the long-term safety of new generations of fillers should be evaluated. OBJECTIVE: This prospective, multicenter, observational, postmarketing study ( ClinicalTrials.gov identifier: NCT04738019) aimed to investigate the incidence of delayed-onset nodules and adverse reactions after the injection of new hyaluronic acid fillers (YYS series) into the facial skin. METHODS: Subjects scheduled to receive an injection YYS series filler were followed up for 52 weeks. The authors aimed to determine the incidence of a self-reported delayed-onset nodule-a visible or palpable nodule or mass at the injection site that was detected beyond the 14th day following the injection-during the 1-year follow-up period. RESULTS: Among the 1,022 subjects who received an injection of the YYS series, the incidences of delayed-onset nodules were 0% for YYS 360, YYS 540, and YYS 720. A 0.21% incidence (1 delayed hypersensitivity reaction) of a delayed-onset adverse reaction was noted for YYS 720, although none were reported for YYS 360 and YYS 540. CONCLUSION: In this study, a notably low frequency of adverse reactions associated with the YYS series was observed.

Relevance of Adalimumab Product Attributes to Patient Experience in the Biosimilar Era: A Narrative Review.

Adalimumab (ADL, Humira®, reference product), an anti-TNF-α biologic, has transformed the treatment of chronic, immune-mediated inflammatory diseases. However, the high cost of ADL therapy has driven the development of more affordable ADL biosimilars, agents with no clinically meaningful differences from the reference product. This review summarizes the product attributes of reference ADL and the nine ADL biosimilars approved and available in the USA in relation to patient experience of injection-site pain (ISP). Product formulation, delivery volume and device features (e.g., type and needle gauge size) influence patient experience of ISP with potential clinical consequences. Citrate-free formulations generally cause less ISP; injection volumes of > 1.5 ml may be associated with increased ISP. Reference ADL and all ADL biosimilars offer a citrate-free formulation, and reference ADL and four ADL biosimilars offer a high-concentration solution that allows a smaller injection volume. All available ADL products are injected subcutaneously using either a pre-filled pen (PFP) or pre-filled syringe (PFS). Patients prefer the PFP, but the PFS permits better control over the speed and duration of injection. Smaller (29-gauge) needle outer diameter is associated with less ISP; reference ADL and seven ADL biosimilars offer a device with a 29-gauge needle. In the USA, an approved biosimilar can be designated "interchangeable," allowing pharmacy-level substitution, where state law permits. In the USA, two ADL biosimilars have received interchangeability designation; others are seeking interchangeability designation from the Food and Drug Administration (n = 2), are being evaluated in clinical studies to support interchangeability (n = 2), or do not have/are not seeking interchangeability designation (n = 3). Product-related attributes influence patient experience of ISP caused by subcutaneous ADL injection. Reference ADL and ADL biosimilar products differ in their attributes, so discussion with patients about treatment options is essential to optimize adherence and outcomes.

Favorable Virological Outcome, Characteristics of Injection Site Reactions, Decrease in Renal Function Biomarkers in Asian People with HIV Receiving Long-Acting Cabotegravir Plus Rilpivirine.

Long-acting cabotegravir plus rilpivirine has revolutionized the concept of antiretroviral therapy, but as the causes of virological failure and satisfaction can depend on patient background, real-world data are needed. In this single-center study, we reviewed clinical records of people with HIV (PWH) who received injectable cabotegravir plus rilpivirine between June 2022 and January 2023. We assessed virological and safety outcomes, including injection site reactions (ISRs) and changes in serum creatinine and cystatin C. Seventy-four patients were included. There were no virological failures. Approximately 80% of individuals achieved HIV-RNA undetectable in all visits up to 14 months (median 13 months) after switching. Pain upon injection was significantly more common at the rilpivirine injection site, while delayed pain was significantly more common at the cabotegravir injection site. The serum creatinine (mean difference -0.12 mg/dL, p < .0001) and the cystatin C (mean difference -0.077 mg/dL, p < .0001) decreased significantly after switching, and in multivariable regression analysis, baseline characteristics did not affect the decrease in these renal function markers. Long-acting cabotegravir plus rilpivirine showed excellent antiviral efficacy and safety in PWH in Japan. ISRs were characterized differently at the cabotegravir and rilpivirine injection sites. Although cystatin C showed decrease after the regimen switch, further confirmation is needed whether cabotegravir plus rilpivirine can improve renal function.

Adverse Events Associated with Hyaluronic Acid Filler Injection for Non-surgical Facial Aesthetics: A Systematic Review of High Level of Evidence Studies.

BACKGROUND: Hyaluronic acid (HA) dermal fillers are widely used in aesthetic medicine. While generally safe, potential complications can arise. OBJECTIVE: This systematic review aims to identify and classify potential complications linked to the use of HA dermal fillers, as informed by high-quality, low-risk-of-bias studies. METHODS: This review follows the Cochrane review standards for clinical systematic reviews. This systematic review analyzed 48 high level of evidence studies on the use of hyaluronic acid (HA) dermal fillers in non-surgical facial aesthetics and the adverse events that occurred.The inclusion criteria were randomized control studies on HA dermal fillers and their complications. Excluded were case reports, case series, observational studies, and other non-randomized research due to their inability to provide generalized conclusions and their inherent publication bias. RESULTS: Adverse events were classified into three categories: expected reactions, product or technique-related adverse events, and severe adverse events. Most adverse events were short-lived injection site reactions, which resolved spontaneously. Specific HA fillers and injection techniques influenced the occurrence of adverse events, which generally resolved within weeks without treatment. Severe adverse events were rare, persisting for months and requiring active medical intervention. DISCUSSION: This classification system can enhance understanding, prevention, and treatment of HA filler complications, and support patient education. The common complications were injection site reactions, with persistent symptoms treated with topical steroids, NSAIDs, or hyaluronidase. Severe complications included severe edema, angioedema and others, often necessitating specific treatments. CONCLUSION: HA dermal fillers are generally safe and effective, with most adverse events being transient and mild to moderate in severity. Severe adverse events, although rare, do occur and are generally non-treatment related. Informed consent, patient education, and professional training are crucial for safe and successful outcomes. Level of Evidence II This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.

CONTEXT: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. OBJECTIVE: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. METHODS: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. RESULTS: TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. CONCLUSION: Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.

A Systematic Review and Meta-Analysis of Injection Site Reactions in Randomized-Controlled Trials of Biologic Injections.

BACKGROUND: Biologic agents are emerging as an important treatment option for immune-mediated diseases. Injection site reactions following subcutaneous injection of biologic agents is not well described in the literature. OBJECTIVE: To summarize injection site reaction data in phase 3 trials of all biologic agents. METHODS: MEDLINE, Embase, and CENTRAL databases were systematically searched on February 8, 2022. Proportional meta-analysis was conducted to summarize injection site reaction prevalence for each biologic. RESULTS: There were 158 articles included in the review. The most common types of injection site reactions were erythema (42.8%), unspecified reaction (23.3%), pain (12.4%), and pruritus (5.7%). No patients discontinued their treatment due to injection site reactions in 39 of the 48 studies that reported on discontinuation data. There were 16 biologics included in meta-analysis across 80 eligible studies. The biologics with the highest point prevalence of patients reporting injection site reactions were Canakinumab (15.5%; 294 patients), Dupilumab (11.4%; 1888 patients), Etanercept (11.4%; 4363 patients), and Ixekizumab (11.2%; 2205 patients). The biologics with the lowest point prevalence of injection site reactions were Risankizumab (0.8%; 707 patients), Brodalumab (1.3%; 1365 patients), Guselkumab (1.3%; 1852 patients), Secukinumab (1.9%; 1277 patients). CONCLUSIONS: The prevalence of injection site reaction in response to biologics ranges from 0.08 to 15.5%. Canakinumab, Dupilumab, Etanercept, and Ixekizumab had the highest prevalence of injection site reactions. Risankizumab, Brodalumab, Guselkumab, and Secukinumab had the lowest prevalence of injection site reactions. Recommendations are made regarding the improvement of adverse event reporting to better understand the epidemiology of injection site reactions.

Comparison of the local safety of two multi-component feline vaccines, adjuvanted (1 mL) versus non-adjuvanted at reduced volume (0.5 mL), using computed tomography imaging.

In 2020, a new 0.5 mL presentation of PUREVAX® RCP FeLV was registered and introduced in Europe. The objectives of this study were to investigate the local safety of this non-adjuvanted vaccine at reduced volume by classical methods (clinical examination, histopathology) and to evaluate the suitability of an alternative non-invasive methodology, the computed tomography (CT). For this purpose, the course of local reactions was assessed for 3 months after subcutaneous injection of PUREVAX® RCP FeLV 0.5 mL and compared to an adjuvanted vaccine, LEUCOFELIGEN® FeLV/RCP 1.0 mL. Injection site reactions consisted mainly of swelling reactions, which were more frequent, more pronounced and long-lasting in the adjuvanted vaccine group. Microscopically, in this group, moderate to severe inflammatory reactions were observed on day 7 (D7) and D21 post-injection and still present on D84, while mild inflammatory lesions were observed in the non-adjuvanted vaccine group only on D7 and D21. With the adjuvanted vaccine, inflamed areas were measurable by CT scan in all cats on D7 and D21, whereas they were detected only on D7 and only in 20 % of cats from the non-adjuvanted vaccine group. Besides the higher frequency, the mean inflamed volume was nearly 300 times larger in adjuvanted vaccine group on D7. Using different methodologies, the favorable safety profile of PUREVAX® RCP FeLV 0.5 mL was confirmed. Furthermore, the vaccine is aligned with current vaccination guidelines by inducing less inflammatory reactions, being adjuvant-free and injectable under a reduced volume, thus improving the convenience of administration in recommended sites (eg, legs). CT scan proved to be a suitable non-invasive method for the experimental follow-up of injection site reactions, yielding results consistent with clinical assessment and histopathology on D7 and D21. CT scan substantiated large differences between the investigated vaccines with a more prominent inflammatory reaction after injection of an adjuvanted vaccine.

PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL.

BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options. METHODS: R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide. FINDINGS: We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin. INTERPRETATION: This immunotherapy combination was found to be active and safe in this clinically challenging patient population.

Comparison of Quality of Life and Injection Site Reactions After Switching from Degarelix 80 mg to 480 mg in Advanced Prostate Cancer: A Prospective Trial.

BACKGROUND/AIM: Degarelix has been widely used for prostate cancer; however, injection site reactions (ISRs) can be a clinical issue. We assessed differences in ISR intensity and patient quality of life (QOL) between degarelix 80 mg and 480 mg, a three-month formulation launched in 2020 in Japan. PATIENTS AND METHODS: We prospectively analyzed 25 patients with advanced prostate cancer. ISR intensity and patient QOL were evaluated before and after switching from degarelix 80 mg to 480 mg. A visual analogue scale (VAS) and faces rating scale (FRS) were applied to assess the ISRs. We applied a rating format from the M. D. Anderson Symptom Inventory (MDASI) to assess patient QOL. RESULTS: For degarelix 80 mg and a first dose of 480 mg, the incidence rate of ISRs was 84% and 92%, respectively (p=0.083). ISR pain on the third day after injection scored by VAS was 2.7±2.8 and 5.2±2.7, respectively (p<0.001). Other ISR findings such as redness, induration, swelling, warmth, and itching were significantly worse for degarelix 480 mg than for 80 mg. In the category of patient QOL, interference with activities of daily living such as general activity was significantly worse after degarelix 480 mg (p=0.003). However, 80% of patients were able to continue degarelix 480 mg during the nine months of follow-up. CONCLUSION: Degarelix 480 mg seems to exacerbate pain and other ISR findings, and to reduce patient QOL, compared with degarelix 80 mg. Optimal management of ISRs is essential to maintain patient QOL when using degarelix 480 mg.

Post-marketing surveillance study of the safety of the HPV-16/18 vaccine in Korea (2017-2021).

Human papillomavirus (HPV) infection is associated with the risk of developing certain cancers, including cancers of the cervix, vulva, vagina, penis, anus, rectum, and oropharynx. In 2016, the bivalent HPV-16/18 vaccine was included in the Korea National Immunization Program. This vaccine protects against HPV types 16 and 18 and other oncogenic HPV types predominant in cervical and anal cancers. This post-marketing surveillance (PMS) study assessed the safety of the HPV-16/18 vaccine in Korea. The study was conducted in males and females aged between 9 and 25 years, from 2017 to 2021. Safety was measured in terms of frequency and intensity of adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs) after each vaccine dose. The safety analysis included all participants who were vaccinated as per prescribing information and who completed a 30-day follow-up after at least one dose. Data were collected using individual case report forms. The total safety cohort included 662 participants. A total of 220 AEs were reported in 144 subjects (21.75%), and there were 158 ADRs in 111 subjects (16.77%), with the most common being injection site pain in all cases. No SAEs or serious ADRs were reported. Most AEs were reported after the first dose and were injection site reactions with mild intensity that recovered. No individuals required hospitalization or an emergency department visit. Safety results showed that the HPV-16/18 vaccine was generally well tolerated in the Korean population, and no safety concerns were identified.ClinicalTrials.gov Identifier: NCT03671369.

What is the context? Infection with human papillomavirus (HPV) is linked to the development of certain cancers.More specifically, HPV types 16 and 18 are predominant in cervical and anal cancers.In 2016, the HPV-16/18 vaccine was included in the National Immunization Program of Korea.What is new? The objective of this study was to evaluate the safety of the HPV-16/18 vaccine following its introduction in Korea.The study was conducted from 2017 to 2021 in young Korean men and women between 9 and 25 years of age.The study analyzed 662 participants, of whom: ∘ 144 reported 220 adverse events∘ 111 reported 158 adverse drug reactions∘ None reported serious adverse eventsThe safety of the vaccine was measured after each dose as the number and intensity of: ∘ Adverse events, which are side-effects or unwanted reactions that might be associated with the use of the vaccine∘ Adverse drug reactions, which are side-effects or unwanted reactions associated with the use of the vaccine∘ Serious adverse events, which are reactions resulting in death, disability, are life-threatening, or require hospitalization (or prolongation of it).Most adverse events occurred following the first dose, were mild in intensity, and the participants recovered after a few days. Injection site pain was the most common adverse event following vaccination.What is the impact?The study showed that the HPV-16/18 vaccine is safe and generally well tolerated in Korean participants.

Metallothionein expression in feline injection site fibrosarcomas.

BACKGROUND: Feline injection site fibrosarcoma is an aggressive and infiltrative tumour arising in the background of chronic inflammation. The aim of this study was to evaluate the expression of metallothionein (I-II) in feline injection site fibrosarcomas and to assess its possible relationships with Ki67 index, inflammation score and tumour grade. The study included 40 feline fibrosarcomas, located in the common injection sites (i.e., interscapular area, thigh, flank), constituting archival diagnostic specimens collected between 2019-2020. Tumours were graded histologically according to the newly proposed soft-tissue sarcoma grading system in cats. Immunohistochemistry was performed to evaluate the expression of Ki67 and metallothionein in tumour cells. RESULTS: The cytoplasmic and sometimes nuclear expression of metallothionein was observed in all tumours grade I, 66.67% of tumours grade II and 55% of tumours grade III. The expression of metallothionein was negatively correlated with tumour grade and inflammation score, while the Ki67 index was positively correlated with tumour grade, inflammation score and necrosis score. CONCLUSION: The downregulation of MT expression in feline injection site fibrosarcomas seems to be connected with an increase in the inflammatory infiltration, hence tumour progression. This is the first study describing metallothionein expression in feline injection site fibrosarcomas.

Analysis and visualization of the course and burden over time of adverse drug reactions (ADRs) attributed to TNFα-inhibitors in patients with inflammatory rheumatic diseases (IRDs).

BACKGROUND: We aimed to investigate course and burden over time of ADRs attributed to TNFα-inhibitors in IRD-patients, and whether Sankey diagrams and polar plots can visualize this. RESEARCH DESIGN AND METHODS: Data on ADRs experienced during the Dutch Biologic Monitor (January 2017 till December 2022) were used in this study. We selected IRD-patients using a TNFα-inhibitor, reporting skin reactions/infections/injection site reactions and completing ≥3 questionnaires (i.e. the initial report and ≥2 follow-ups). Course was scored as worsening/improving/remaining stable/resolving and as (non-)recurrent. Patients scored burden from 1 (no burden) to 5 (very high burden). Sankey diagrams and polar plots visualized this. RESULTS: 202 patients were included, reporting 353 ADRs. Most skin reactions were stable (25.0%). Most infections resolved (50.8%). Injection site reactions were mostly recurrent (72.3%). Skin reactions and infections tended to decrease in burden . Infections had highest burden at start, which mostly decreased over time. Injection site reactions had a low and stable burden. CONCLUSIONS: Skin reactions attributed to TNFα-inhibitors by IRD-patients are stable with a slightly decreasing burden over time. Infections have highest burden at start but resolved mostly. Injection site reactions have a low and stable burden. Sankey diagrams and polar plots are suitable to visualize this.

A randomised phase II trial of a trivalent ganglioside vaccine targeting GM2, GD2 and GD3 combined with immunological adjuvant OPT-821 versus OPT-821 alone in metastatic sarcoma patients rendered disease-free by surgery.

BACKGROUND: Recurrence after resection of metastatic sarcoma is common. The gangliosides GM2, GD2 and GD3 are strongly expressed across sarcoma subtypes. We hypothesised that generation of anti-ganglioside antibodies would control micrometastases and improve outcomes in sarcoma patients who were disease-free after metastasectomy. METHODS: We conducted a randomised phase II trial of the immunological adjuvant OPT-821 with a KLH-conjugated ganglioside vaccine targeting GM2, GD2 and GD3, versus OPT-821 alone in patients with metastatic sarcoma following complete metastasectomy. Patients received 10 subcutaneous injections at Weeks 1, 2, 3, 8, 16, 28, 40, 52, 68 and 84 and were followed for evidence of recurrent disease. The primary end-point was relapse-free survival. Secondary end-points included overall survival and serologic response. RESULTS: A total of 136 patients were randomised, 68 to each arm. The mean age was 51.2, 52.2% were male, 90.4% had relapsed disease, 86.8% had high-grade tumours and 14% had ≥4 metastases resected. Histologies included leiomyosarcoma (33%), spindle cell sarcoma (14%), undifferentiated pleomorphic sarcoma (13%), osteosarcoma (10%), synovial sarcoma (9%), liposarcoma (9%) and others (12%). Most adverse events were Grade ≤2 (83.8% and 70.6% in the vaccine and adjuvant arms, respectively). The most common (≥20% of patients) were injection site reaction (89.7%), fatigue (44.1%) and pyrexia (27.9%) on the vaccine arm, and injection site reaction (69.1%) on the adjuvant only arm. The 1-year relapse-free survival rate (34.5% and 34.8% in the vaccine and OPT-821 monotherapy arm, respectively) did not differ between arms (P = 0.725). One-year overall survival rates were 93.1% and 91.5% in the vaccine and OPT-821 monotherapy arm, respectively (P = 0.578). Serologic responses at week 9 were more frequent on the vaccine arm (96.5% of patients) than in the adjuvant arm (32.8%), and the difference between groups was durable. CONCLUSIONS: A sustained serologic response to vaccination was induced with the vaccine, but no difference in recurrence-free or overall survival was observed between treatment arms. CLINICALTRIALS: gov identifier: NCT01141491.

Restylane Lyft for Aesthetic Shaping of the Nasal Dorsum and Radix: A Randomized, No-Treatment Control, Multicenter Study.

BACKGROUND: Hyaluronic acid fillers are widely used in nonsurgical rhinoplasty. METHODS: The authors performed a no-treatment control, multicenter, 12-month follow-up study to evaluate efficacy and safety of Restylane Lyft (Galderma, Uppsala, Sweden) in shaping the nasal dorsum and radix. Assignment to Restylane Lyft or no-treatment control was randomized (3:1). The Restylane Lyft group received a maximum of 1 ml of Restylane Lyft on day 1; the control group was offered a maximum of 1 ml of Restylane Lyft at month 6. Both groups were offered re-treatment (a maximum of 0.5 ml of Restylane Lyft) at month 12. Outcome assessments included blinded evaluation of three-dimensional photography measurements of change in volume (primary endpoint; month 6) and elevation of the nasal dorsum and radix, aesthetic improvement, adverse events, and diary-reported injection-site reactions. RESULTS: One hundred thirty-two Chinese subjects were enrolled. The Restylane Lyft group had a greater increase in volume of the nasal dorsum and radix than the no-treatment control (mean difference at month 6, 0.71 ml; 95 percent confidence interval, 0.59 to 0.83 ml; p < 0.001). Restylane Lyft was also more effective than no-treatment control in achieving an elevation of the nasal dorsum and radix. The increase in volume and elevation persisted up to 12 months after injection and was supported by clinical assessments of aesthetic improvement. Treatment-related adverse events were mild to moderate, nonserious, and resolved during the study. Injection-site reactions were mostly mild to moderate and resolved within 1 week. CONCLUSION: Restylane Lyft injection was effective for aesthetic shaping of the nasal dorsum and radix and achieved aesthetic improvement for up to 12 months with an acceptable safety profile. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

Ixekizumab Citrate-Free Formulation: Results from Two Clinical Trials.

INTRODUCTION: Subcutaneous (SC) injection is a common route of drug administration; however, injection site pain (ISP) might create a negative patient experience. We evaluated ISP, bioequivalence, and overall safety of the citrate-free (CF) formulation of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A. METHODS: Two phase 1, single-blind studies were conducted in healthy participants. The crossover study A (NCT03848403) evaluated pain intensity on injection as measured by visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the beginning to three possible treatment sequences and received a 1 mL SC injection of the three formulations sequentially in the abdomen on days 1, 8, and 15, respectively. A mixed-effects repeated measures analysis model was used to analyze VAS score by time post-injection. Study B (NCT04259346) evaluated the bioequivalence of a single 80 mg dose of CF formulation compared to the original commercial formulation. Subjects (N = 245) were randomized 1:1 to either commercial or CF formulation and received a single SC injection into the abdomen, arm, or thigh. RESULTS: Primary endpoint was achieved in both studies. In study A, least-squares mean (LSM) difference of VAS scores immediately post injection between commercial (n = 61) and CF formulation (n = 63) was - 21.7 (p < 0.0001), indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence of the CF formulation was established as 90% CIs for the ratio of geometric LSM AUC0-tlast, AUC0-∞, and Cmax between treatments were contained within the prespecified limits of 0.8 and 1.25. Except for less ISP in the CF formulation, overall safety profile was comparable. CONCLUSION: Ixekizumab CF formulation proved to be bioequivalent, was associated with less ISP, and had no other notable differences in the safety profile compared to the original commercial formulation. TRAIL REGISTRATION: ClinicalTrials.gov identifier NCT03848403, NCT04259346.

Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB). METHODS: A retrospective chart review was conducted for patients treated with obinutuzumab from January 1, 2014 to December 31, 2017 at CCMB. A minimum data set was extracted for patients treated with other front-line therapies. Descriptive statistics were used to evaluate patient demographics, toxicity, duration and dosing of obinutuzumab treatment. Kaplan-Meier curves were used to evaluate time-to-next-treatment (TTNT), overall survival (OS) and PFS for patients treated with obinutuzumab. A multivariable logistic regression model was used to investigate associations between infusion related reactions (IRRs) and age at treatment, pre-treatment lymphocyte count, cumulative illness rating scale (CIRS) and receipt of prior chemotherapy. RESULTS: Forty seven percent of patients receiving frontline therapy received chlorambucil and obinutuzumab. Sixty-seven patients were treated with obinutuzumab and consisted of 36 males (53.7%) and 31 females (46.3%) with 29 patients (43.3%) over age 75 years. Rates of grade 3 and 4 obinutuzumab IRRs were lower (6%) compared to the CLL11 clinical trial (20%) due to local practices including slower infusion rates and using chlorambucil before starting obinutuzumab treatment. Many patients had difficulty tolerating the full dosage of chlorambucil. Only 26 patients (38.8%) had their dose of chlorambucil escalated to the full dose of 0.5 mg/kg. In addition, only 18 patients (26.9%) received all doses of obinutuzumab and all 12 doses of chlorambucil. CONCLUSIONS: In summary, first dose infusion reactions with obinutuzumab can be markedly reduced by using chlorambucil to decrease the lymphocyte count before obinutuzumab and by using a very slow initial obinutuzumab infusion rate. Modifications in chlorambucil dosing and obinutuzumab administration can improve tolerance without significant loss in efficacy.

Heterologous AD5-nCOV plus CoronaVac versus homologous CoronaVac vaccination: a randomized phase 4 trial.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and the waning of vaccine-elicited neutralizing antibodies suggests that additional coronavirus disease 2019 (COVID-19) vaccine doses may be needed for individuals who initially received CoronaVac. We evaluated the safety and immunogenicity of the recombinant adenovirus type 5 (AD5)-vectored COVID-19 vaccine Convidecia as a heterologous booster versus those of CoronaVac as homologous booster in adults previously vaccinated with CoronaVac in an ongoing, randomized, observer-blinded, parallel-controlled phase 4 trial ( NCT04892459 ). Adults who had received two doses of CoronaVac in the past 3-6 months were vaccinated with Convidecia (n = 96) or CoronaVac (n = 102). Adults who had received one dose of CoronaVac in the past 1-3 months were also vaccinated with Convidecia (n = 51) or CoronaVac (n = 50). The co-primary endpoints were the occurrence of adverse reactions within 28 d after vaccination and geometric mean titers (GMTs) of neutralizing antibodies against live wild-type SARS-CoV-2 virus at 14 d after booster vaccination. Adverse reactions after vaccination were significantly more frequent in Convidecia recipients but were generally mild to moderate in all treatment groups. Heterologous boosting with Convidecia elicited significantly increased GMTs of neutralizing antibody against SARS-CoV-2 than homologous boosting with CoronaVac in participants who had previously received one or two doses of CoronaVac. These data suggest that heterologous boosting with Convidecia following initial vaccination with CoronaVac is safe and more immunogenic than homologous boosting.