Safety of Secukinumab from 1 Million Patient-Years of Exposure: Experience from Post-Marketing Setting and Clinical Trials.

INTRODUCTION: Secukinumab is an anti-interleukin (IL)-17A monoclonal antibody indicated for multiple immunological disorders. Here, we aim to summarize secukinumab safety in clinical trials (CTs) and post-marketing setting (PMS) until 25 June 2022. METHODS: Adverse events (AEs) were summarized with crude reporting rate (RR) per 100 patient-years (PY) in PMS for all reported indications and with exposure-adjusted incident rates (EAIR) per 100 PY in pooled 47 CTs for approved indications. RESULTS: Secukinumab exposure totaled 1,159,260 PY in PMS and 27,765 PY in CTs. AEs were mostly (> 80%) non-serious in PMS. EAIR for serious AEs was 7.0/100 PY. Nasopharyngitis (RR 0.59/100 PY, EAIR 16.08/100 PY) and pneumonia (RR 0.14/100 PY, EAIR 0.17/100 PY) were the most common infection and serious infection, respectively. Candida infections (RR 0.20/100 PY, EAIR 2.16/100 PY) were the most common fungal infections. Inflammatory bowel disease (IBD) was observed in PMS (0.14/100 PY) and CTs (0.26/100 PY). Most (76%) patients with prior IBD did not report IBD flare during CTs. PMS monitoring identified paradoxical skin reactions including dyshidrotic eczema (RR 0.006/100 PY) and pyoderma gangrenosum (RR 0.003/100 PY). CONCLUSION: Secukinumab safety profile with increased patient exposure remained favorable. Paradoxical skin reactions were identified in post-marketing monitoring.

Safety and efficacy of secukinumab in patients with giant cell arteritis (TitAIN): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis. METHODS: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion. Participants were assigned (1:1) to receive 300 mg secukinumab or placebo subcutaneously once a week up to week 4 and every 4 weeks thereafter. In both treatment groups, prednisolone dose was tapered down to 0 mg over a 26-week period. Patients, investigator staff, and clinical trial team were masked to the treatment assignment. The primary endpoint was the median proportion (Bayesian analysis) of patients with sustained remission until week 28 in the full analysis set (ie, all patients who received at least one dose of assigned treatment, analysed according to treatment assigned at randomisation). Sustained remission rate of the placebo group from a previous trial of tocilizumab in patients with giant cell arteritis was used to derive the prior distribution of placebo sustained remission rate for the primary endpoint. The safety of secukinumab was assessed in the safety set (ie, all patients who received at least one dose of study treatment, analysed according to study treatment received). This trial is completed and is registered with ClinicalTrials.gov, NCT03765788. FINDINGS: Of the 65 patients who were assessed for eligibility, 52 patients (median age 75 years [IQR 69-79]; 35 [67%] female and 17 [33%] male, 52 [100%] White) were enrolled between Jan 30, 2019 and March 30, 2020 and were randomly assigned to receive secukinumab (n=27) or placebo (n=25). Four of 27 patients in the secukinumab group and eight of 25 patients in the placebo group discontinued treatment by week 28 of the study. On the basis of the Bayesian analysis, the median proportion of patients in sustained remission until week 28 was 70% (95% credibility interval 52-85) in the secukinumab group versus 20% (12-30) in the placebo group. The incidence of adverse events was similar in the secukinumab (27 [100%] of 27 patients had any adverse event) and placebo groups (24 [96%] of 25 patients had any adverse event); the most common adverse events were hypertension (six [22%] of 27 patients in the secukinumab group and eight [32%] of 25 patients in the placebo group) and nasopharyngitis (five [19%] of 27 patients in the secukinumab group and five [20%] of 25 patients in the placebo group). Two patients (one in each group) died during the study, neither of which was considered to be related to study treatment. INTERPRETATION: Patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, in combination with glucocorticoid taper regimen. Secukinumab was tolerated well with no new safety concerns. This proof-of-concept phase 2 study further supports the development of secukinumab as a treatment option for people with giant cell arteritis. FUNDING: Novartis Pharma.

Patient-reported impact of chronic urticaria compared with psoriasis in theUnited States.

PURPOSE: Data are lacking on the burden of chronic idiopathic urticaria (CIU) versus other dermatologic conditions. This analysis compared the burden of chronic urticaria (CU, proxy for CIU) with psoriasis. METHODS: Data from CU (N = 747) and psoriasis patients (N = 5107) came from 2010 to 2012 US National Health and Wellness Surveys. Outcomes included SF-12v2/SF-36v2 mental and physical component summary scores (MCS and PCS, respectively) and other health/activity-related measures. RESULTS: MCS score was 44.7 for CU, and 48.2, 44.7 and 44.3 for mild/moderate/severe psoriasis, respectively (US norm = 50). PCS score was 43.8 for CU, and 46.5, 44.1 and 40.3 for mild/moderate/severe psoriasis. Health utility score was 0.67 for CU, and 0.72, 0.67 and 0.65 for mild/moderate/severe psoriasis. More CU patients reported depression (39%), anxiety (42%) and sleep difficulties (50%) than psoriasis patients (any severity). Overall work impairment was 29% for CU, and 19%, 26% and 31% for mild/moderate/severe psoriasis. Activities impairment was 39% for CU, and 28%, 37% and 43% for mild/moderate/severe psoriasis. CU and psoriasis patients had frequent healthcare visits. CONCLUSIONS: Patients with CU had impaired mental/physical health and work/non-work activities, similar to moderate-to-severe psoriasis patients. Results suggest that better disease management of CU is needed. This analysis should also reflect the significant burden of CIU.

Telbivudine vs tenofovir in hepatitis B e antigen-negative chronic hepatitis B patients: OPTIMA roadmap study.

AIM: To make efficacy and safety comparison of telbivudine-raodmap and tenofovir-roadmap in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. METHODS: This was the first prospective, randomised, two-arm, open-label, non-inferiority study in HBeAg-negative CHB patients that compared telbivudine and tenofovir administered as per roadmap concept. Patients were treated up to 24 wk and, depending on virologic response, continued the same therapy or received add-on therapy up to 104 wk. Eligible patients received an additional 52 wk of treatment in the extension period (i.e., up to 156 wk). Patients who developed virologic breakthrough (VB) while on monotherapy also received add-on therapy. The primary efficacy endpoint was the rate of patients achieving hepatitis B virus (HBV) DNA < 300 copies/mL at week 52. Secondary efficacy endpoints included the rates of HBV DNA < 300 and < 169 copies/mL, HBV DNA change from baseline, alanine aminotransferase normalisation, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, VB, and emergence of resistance at various timepoints throughout the study. Safety and estimated glomerular filtration rate (eGFR) were also analysed. RESULTS: A total of 241 patients were randomised. Non-inferiority of telbivudine arm to tenofovir arm was demonstrated at week 52 (± 7 d window), with over 91% of patients in each treatment arm achieving HBV DNA level < 300 copies/mL. Both arms were similar in terms of key secondary efficacy variables at weeks 104 and 156. The percentage of patients achieving HBV DNA < 300 copies/mL remained high and was similar in the telbivudine and tenofovir arms at both weeks 104 and 156. Over 82% of patients in both arms achieved alanine aminotransferase normalisation at week 52, and this percentage remained high at weeks 104 and 156. Telbivudine treatment progressively reduced serum HBsAg levels from baseline while no change was reported in quantitative HBsAg during therapy with tenofovir. Both treaments showed acceptable safety profiles. The telbivudine arm showed eGFR improvement unlike the tenofovir arm. CONCLUSION: Efficacy was shown for both telbivudine-roadmap and tenofovir-roadmap regimens in HBeAg-negative CHB patients over 156 wk. Telbivudine arm was associated with renal improvement.

Angioedema in the omalizumab chronic idiopathic/spontaneous urticaria pivotal studies.

BACKGROUND: Angioedema, present in some patients with chronic idiopathic/spontaneous urticaria (CIU/CSU), may have a negative effect on patient quality of life. OBJECTIVE: To describe patient-reported angioedema and its management in the pivotal omalizumab studies (ASTERIA I, ASTERIA II, GLACIAL). METHODS: Enrolled patients with CIU/CSU remained symptomatic despite treatment with histamine1 (H1)-antihistamines at licensed doses (ASTERIA I, ASTERIA II) or H1-antihistamines at up to 4 times the approved dose plus H2-antihistamines and/or a leukotriene receptor antagonist (GLACIAL). All studies administered omalizumab (75, 150, or 300 mg in ASTERIA I and ASTERIA II; 300 mg in GLACIAL) or placebo subcutaneously every 4 weeks for at least 12 weeks. Urticaria Patient Daily Diary entries were completed by patients and summarized. RESULTS: At baseline, angioedema prevalence was higher in GLACIAL (53.1%) than in ASTERIA I (47.5%) or ASTERIA II (40.7%). The mean proportion of angioedema-free days during weeks 4 to 12 was greater for patients treated with 300 mg of omalizumab than placebo in ASTERIA I (96.1% vs 88.2%, P < .001), ASTERIA II (95.5% vs 89.2%, P < .001), and GLACIAL (91.0% vs 88.7%, P = .006). Most patient-reported angioedema was managed by low-intensity interventions (doing nothing or taking medication). CONCLUSION: Treatment with 300 mg of omalizumab was efficacious in reducing patient-reported angioedema. Low-intensity interventions were generally used to manage angioedema episodes. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01287117 (ASTERIA I), NCT01292473 (ASTERIA II), and NCT01264939 (GLACIAL).

Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.

RATIONALE: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial. OBJECTIVES: Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP. METHODS: A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours. MEASUREMENTS AND MAIN RESULTS: Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups. CONCLUSIONS: Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.

Early microbiological response to linezolid vs vancomycin in ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of ventilator-associated pneumonia (VAP). This prospective, open-label, multicenter clinical trial compared the early microbiological efficacy of linezolid (LZD) therapy with that of vancomycin (VAN) therapy in patients with MRSA VAP. METHODS: A total of 149 patients with suspected MRSA VAP were randomized to receive either LZD, 600 mg, or VAN, 1 g every 12 h. Patients with baseline bronchoscopic BAL (BBAL) fluid quantitative culture findings that were positive for MRSA (>or= 10(4) cfu/mL) comprised the study population. The primary outcome was microbiological response (

Antiretroviral drug resistance in human immunodeficiency virus-infected source patients for occupational exposures to healthcare workers.

OBJECTIVE: To assess the prevalence of HIV antiretroviral resistance among source patients for occupational HIV exposures. DESIGN: Blood and data (eg, stage of HIV, previous antiretroviral drug therapy, and HIV RNA viral load) were collected from HIV-infected patients who were source patients for occupational exposures. SETTING: Seven tertiary-care medical centers in five U.S. cities (San Diego, California; Miami, Florida; Boston, Massachusetts; Albany, New York; and New York, New York [three sites]) during 1998 to 1999. PARTICIPANTS: Sixty-four HIV-infected patients who were source patients for occupational exposures. RESULTS: Virus from 50 patients was sequenced; virus from 14 patients with an undetectable (ie, < 400 RNA copies/mL) viral load could not be sequenced. Overall, 19 (38%) of the 50 patients had primary genotypic mutations associated with resistance to reverse transcriptase or protease inhibitors. Eighteen of the 19 viruses with primary mutations and 13 wild type viruses were phenotyped by recombinant assays; 19 had phenotypic resistance to at least one antiretroviral agent. Of the 50 source patients studied, 26 had taken antiretroviral agents in the 3 months before the occupational exposure incident. Sixteen (62%) of the 26 drug-treated patients had virus that was phenotypically resistant to at least one drug. Four (17%) of 23 untreated patients had phenotypically resistant virus. No episodes of HIV transmission were observed among the exposed HCWs. CONCLUSIONS: There was a high prevalence of drug-resistant HIV among source patients for occupational HIV exposures. Healthcare providers should use the drug treatment information of source patients when making decisions about post-exposure prophylaxis.

Adenovirus infection in pediatric small bowel transplantation recipients.

BACKGROUND: The purpose of this study was to determine the prevalence of adenoviral infection in pediatric small bowel transplantation (SBT) recipients, examine risk factors for progression to histologic disease, and examine the impact of adenovirus on outcome. METHODS: Beginning in July 2000, all SBT recipients had viral cultures for adenovirus, cytomegalovirus (CMV), and herpes simplex virus (HSV) obtained routinely during graft biopsies. The medical records were retrospectively reviewed for frequency and site of viral culture, types and doses of immunosuppressive drugs, episodes of rejection, histology of allograft biopsies, and other infections. Adenoviral isolates were typed by polymerase chain reaction and type-specific neutralization assays. RESULTS: All 14 SBT recipients who met enrollment criteria had evidence of adenoviral infection (intestinal graft, 13; liver graft, 1). Eight of 14 developed histologic disease with identifiable adenoviral intranuclear inclusions. In contrast, CMV enteritis was identified in only one patient, who subsequently also developed adenoviral disease. No other viruses were detected. Adenoviral cultures were first positive within 30 days of transplant in nine. Patients with histologic disease were more likely than those without to have received intensive corticosteroid therapy (P<0.007), had virus isolated from more than one site (P=0.03), and had persistent positive cultures (P<0.01). CONCLUSIONS: Adenovirus was commonly isolated from children undergoing intestinal transplantation. Progression to disease may be associated with more intensive immunosuppressive therapy and inability to clear virus.

A comprehensive approach to percutaneous injury prevention during phlebotomy: results of a multicenter study, 1993-1995.

OBJECTIVE: To examine a comprehensive approach for preventing percutaneous injuries associated with phlebotomy procedures. DESIGN AND SETTING: From 1993 through 1995, personnel at 10 university-affiliated hospitals enhanced surveillance and assessed underreporting of percutaneous injuries; selected, implemented, and evaluated the efficacy of phlebotomy devices with safety features (ie, engineered sharps injury prevention devices [ESIPDs]); and assessed healthcare worker satisfaction with ESIPDs. Investigators also evaluated the preventability of a subset of percutaneous injuries and conducted an audit of sharps disposal containers to quantify activation rates for devices with safety features. RESULTS: The three selected phlebotomy devices with safety features reduced percutaneous injury rates compared with conventional devices. Activation rates varied according to ease of use, healthcare worker preference for ESIPDs, perceived "patient adverse events," and device-specific training. CONCLUSIONS: Device-specific features and healthcare worker training and involvement in the selection of ESIPDs affect the activation rates for ESIPDs and therefore their efficacy. The implementation of ESIPDs is a useful measure in a comprehensive program to reduce percutaneous injuries associated with phlebotomy procedures.

Evaluation of a safety resheathable winged steel needle for prevention of percutaneous injuries associated with intravascular-access procedures among healthcare workers.

OBJECTIVE: To compare the percutaneous injury rate associated with a standard versus a safety resheathable winged steel (butterfly) needle. DESIGN: Before-after trial of winged steel needle injuries during a 33-month period (19-month baseline, 3-month training, and 11-month study intervention), followed by a 31-month poststudy period. SETTING: A 1,190-bed acute care referral hospital with inpatient and outpatient services in New York City. PARTICIPANTS: All healthcare workers performing intravascular-access procedures with winged steel needles. INTERVENTION: Safety resheathable winged steel needle. RESULTS: The injury rate associated with winged steel needles declined from 13.41 to 6.41 per 100,000 (relative risk [RR], 0.48; 95% confidence interval [CI95], 0.31 to 0.73) following implementation of the safety device. Injuries occurring during or after disposal were reduced most substantially (RR, 0.15; CI95, 0.06 to 0.43). Safety winged steel needle injuries occurred most often before activation of the safety mechanism was appropriate (39%); 32% were due to the user choosing not to activate the device, 21% occurred during activation, and 4% were due to improper activation. Preference for the safety winged steel needle over the standard device was 63%. The safety feature was activated in 83% of the samples examined during audits of disposal containers. Following completion of the study, the safety winged steel needle injury rate (7.29 per 100,000) did not differ significantly from the winged steel needle injury rate during the study period. CONCLUSION: Implementation of a safety resheathable winged steel needle substantially reduced injuries among healthcare workers performing vascular-access procedures. The residual risk of injury associated with this device can be reduced further with increased compliance with proper activation procedures.

Tuberculin skin testing surveillance of health care personnel.

To estimate the incidence of and assess risk factors for occupational Mycobacterium tuberculosis transmission to health care personnel (HCP) in 5 New York City and Boston health care facilities, performance of prospective tuberculin skin tests (TSTs) was conducted from April 1994 through October 1995. Two-step testing was used at the enrollment of 2198 HCP with negative TST results. Follow-up visits were scheduled for every 6 months. Thirty (1.5%) of 1960 HCP with >/=1 follow-up evaluation had TST conversion (that is, an increase in TST induration of >/=10 mm). Independent risk factors for TST conversion were entering the United States after 1991 and inclusion in a tuberculosis-contact investigation in the workplace. These findings suggest that occupational transmission of M. tuberculosis occurred, as well as possible nonoccupational transmission or late boosting among foreign-born HCP who recently entered the United States. These results demonstrate the difficulty in interpreting TST results and estimating conversion rates among HCP, especially when large proportions of foreign-born HCP are included in surveillance.