Ongoing Post-marketing Surveillance Research Articles

Safety and Effectiveness of Satralizumab in Japanese Patients with Neuromyelitis Optica Spectrum Disorder: A 6-month Interim Analysis of Post-marketing Surveillance.

Satralizumab, an anti-interleukin-6 receptor antibody, is approved in Japan for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and is undergoing post-marketing surveillance (PMS) of clinical use. We aimed to describe the real-world safety and effectiveness of satralizumab in Japanese patients with NMOSD. This is an ongoing PMS (planned completion: February 2027). This 6-month interim analysis assessed the safety and effectiveness of satralizumab in Japanese patients with NMOSD using data collected from August 2020 to July 2021. Among 570 patients who participated, 523 (91.75%) were female and the mean±standard deviation (SD) age was 52.4±14.1years. At baseline, NMOSD expanded disability status scale mean±SD was 4.19±2.19; 490 (85.96%) patients used glucocorticoids and 277 (48.59%) patients used immunosuppressants concomitantly. Of 570 satralizumab-treated patients, 85 (14.91%) had discontinued satralizumab treatment at 6months. For the overall adverse drug reactions (ADRs), 76.22 (66.07-87.48) events/100 person-years occurred in 118 (20.70%) patients, and infections occurred in 28 (4.91%) patients. Serious infections occurred in 18 (3.15%) patients, with an event rate of 9.05 (5.80-13.47) events/100 person-years. Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common serious infection events. One fatal ADR (septic shock) suspected to be related to satralizumab was reported. The mean±SD glucocorticoid dose reduced from 12.28±10.17mg/day at the index date to 8.11±7.30mg/day at 6months. The Kaplan-Meier cumulative relapse-free rate (95% confidence interval) was 94.59% (92.25-96.23) at 6months. In this study, satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice. The results are consistent with those of previous clinical trials. The safety and effectiveness of satralizumab in Japanese patients with NMOSD will be analyzed over the 6-year surveillance period. UMIN Clinical Trials Registry, UMIN000041047.

Safety and effectiveness of guselkumab in Japanese patients with psoriasis: 20-week interim analysis of a postmarketing surveillance study.

A 52-week postmarketing surveillance study was initiated to evaluate the safety and effectiveness of guselkumab, a human anti-interleukin 23 subunit p19 monoclonal antibody, in Japanese patients with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis, and erythrodermic psoriasis in real-world practice. Here, we report results of the 20-week interim analysis of the ongoing postmarketing surveillance study. Patients who received guselkumab between May 2018 (the date of commercial launch in Japan) and October 2020 were registered in this study. In total, 411 and 245 patients were included in the safety and effectiveness analysis sets, respectively. Adverse drug reactions (ADRs) occurred in 6.6% (27 of 411) and serious ADRs in 2.2% (nine of 411) of patients. The most frequent ADRs by System Organ Class were "Infections and infestations" (2.4%), with nasopharyngitis being the most frequently observed ADR (0.7%). The mean Psoriasis Area Severity Index score decreased from 11.6 at baseline to 6.5 at week 4 and 2.2 at week 20, with improvements achieving statistical significance at each time point. Clinical Global Impression, Dermatology Life Quality Index, and Nail Psoriasis Severity Index outcomesalso showed substantial improvements. Our findings demonstrate that guselkumab is well tolerated and effective in Japanese patients with psoriasis through 20 weeks of treatment in real-world clinical practice, showing significant effectiveness observed as early as 4 weeks. The study was officially registered with the University Hospital Medical Information Network Clinical Trials Registry with the identifier UMIN000032969.

Safety and Effectiveness of Vedolizumab in Patients with Moderate-to-Severe Ulcerative Colitis: An Interim Analysis of a Japanese Post-Marketing Surveillance Study.

This ongoing post-marketing surveillance monitors the long-term safety and effectiveness of vedolizumab in routine clinical practice in patients with moderate-to-severe ulcerative colitis (UC) in Japan. This interim analysis assessed induction-phase data, covering the initial three doses of vedolizumab. Patients were enrolled via a web-based electronic data capture system from approximately 250 institutions. Incidence of adverse events and treatment responses were assessed by the physicians after the patient had received three doses of vedolizumab or when the drug was discontinued, whichever occurred first. Therapeutic response was defined as any treatment response, including remission or improvement of complete or partial Mayo score, and was assessed in the total and stratified patient populations according to prior tumor necrosis factor alpha (TNFα) inhibitor treatments and/or baseline partial Mayo score. The total incidence of adverse drug reactions (ADRs) was 4.10% (11/268). Common ADRs were dizziness, nausea, and arthralgia, each reported in 0.75% of patients (2/268). Serious ADRs were herpes zoster oticus and UC, each reported in 0.37% of patients (1/268). Therapeutic response was reported in 84.5% (218/258) of all patients, 85.8% (127/148) of TNFα inhibitor-naïve patients, and 82.7% (91/110) of TNFα inhibitor-experienced patients. Among patients with partial Mayo score of ≥ 4 at baseline, partial Mayo score remission in patients without or with prior TNFα inhibitor treatment was 62.5% (60/96) and 45.6% (36/79), respectively. The results confirm a safety and effectiveness profile of vedolizumab consistent with that observed in previous trials. JapicCTI-194603, NCT03824561.

Cardiovascular risks associated with Janus kinase inhibitors: peering outside the black box.

Considerable controversy related to the cardiovascular safety of Janus kinase inhibitors (JAKinibs) has arisen following the results of the ORAL Surveillance trial. In this trial of rheumatoid arthritis (RA) ≥ 50years with at least one prevalent cardiovascular disease (CVD) risk factor, tofacitinib was not found to be non-inferior to tumour necrosis factor-alpha inhibitors (TNFi) with regards to the risk for major adverse cardiovascular events (MACE), venous thromboembolism (VTE) or malignancy. Following the results of ORAL Surveillance, the United States Food and Drug Administration (US FDA) issued a boxed warning regarding increased risks of MACE, VTE and malignancy with tofacitinib, baricitinib or upadacitinib in inflammatory arthritis or ulcerative colitis. Analysis of data from other trials (including long-term follow-up studies) of tofacitinib in RA, psoriasis, psoriatic arthritis, spondyloarthritis and inflammatory bowel diseases suggests an overall similar risk of MACE or VTE with tofacitinib when compared with TNFi. In specific patient populations with risk factors for or prior history of MACE or VTE, the risk of subsequent MACE or VTE with tofacitinib use is considerably heightened. Post-hoc analyses from ORAL Surveillance presented at the recent EULAR meeting further help to delineate patients with RA at increased risk of MACE/VTE with tofacitinib. Based on the available literature from trials and long-term follow-up studies of baricitinib and upadacitinib, there exists insufficient evidence to extend the warning of MACE/VTE with tofacitinib to these drugs. Ongoing post-marketing surveillance studies of JAKinibs in immune-mediated inflammatory diseases should help clarify CVD risk with JAKinibs.

32501 Real-world safety and 1-year effectiveness of dupilumab in Japanese patients with atopic dermatitis: An interim analysis of ongoing regulatory post-marketing surveillance

Objective and methods: Dupilumab, a human monoclonal antibody against the IL-4/13 receptor, has been used in Japan since 2018 for treatment of adult atopic dermatitis (AD) with inadequate response to existing therapies. We report the results of an interim analysis of ongoing post-marketing surveillance that evaluates long-term safety and effectiveness of dupilumab in real-world settings in Japan (UMIN Clinical Trial Registry No. UMIN000032807, data cut-off: March 2021).

Susceptibility of ceftobiprole against Gram-positive and Gram-negative clinical isolates from 2019 from different European territories

Ceftobiprole is approved for use in treatment of hospital-associated and community-acquired pneumonia in 16 different European countries and is currently undergoing clinical trials in the United States. Isolates were collected from hospital laboratories from 16 European countries during 2019 as part of an ongoing post-marketing surveillance study. MICs were determined using EUCAST broth microdilution methodology and interpreted using 2020 EUCAST breakpoints. Ceftobiprole was active (MIC, ≤2 mg/L) against 100% and 99.3% of methicillin-susceptible Staphylococcus aureus and MRSA isolates collected in 2019. Against Streptococcus pneumoniae, ceftobiprole was active (MIC, ≤0.5 mg/L) against 98.4% of isolates. Overall, 77.4% of Enterobacterales were susceptible though isolate numbers in certain countries were notably low. In addition, based on non-species-related PK/PD breakpoints, 69.7% of Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. Analysis of data by geographical regions showed that susceptibility to ceftobiprole by region or country was not significantly varied though MRSA, S. pneumoniae, Enterobacterales and P. aeruginosa. Isolates from Italy had lower susceptibilities to ceftobiprole: 98% of MRSA, 94% of S. pneumoniae and 61% of Enterobacterales isolates were susceptible to ceftobiprole. The data for ceftobiprole for isolates from 2019 are encouragingly very similar to studies performed on isolates from earlier years showing that susceptibility to ceftobiprole has not changed and, importantly, that resistance emergence remains low throughout Europe.

Surveillance of ceftobiprole against Gram-positive and Gram-negative clinical isolates from 2018 from different European territories

Ceftobiprole is approved for the treatment of hospital-acquired and community-acquired pneumonia in 17 different European countries and is currently undergoing clinical trials in the USA. In this study, isolates were collected from hospital laboratories from 15 European countries during 2018 as part of an ongoing post-marketing surveillance study. Minimum inhibitory concentrations (MICs) were determined using European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution methodology and were interpreted using 2019 EUCAST breakpoints. Ceftobiprole was active (MIC, ≤2 mg/L) against 100% and 98.9% of methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) from 2018, respectively. Only six MRSA isolates (1.1%) were resistant to ceftobiprole and originated from four countries. Against Streptococcus pneumoniae, ceftobiprole was active (MIC, ≤0.5 mg/L) against 98.7% of isolates. Overall, 75.6% of Enterobacterales were susceptible, although isolate numbers in certain countries were notably low. In addition, based on non-species-related pharmacokinetic/pharmacodynamic breakpoints, 63.2% of Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. Data for ceftobiprole for isolates from 2018 are very similar to studies performed on isolates from earlier years, showing that susceptibility to ceftobiprole has remained high.

No increased risk of glucose metabolism disorders in adults with growth hormone deficiency undergoing long-term treatment with biosimilar somatropin (Omnitrope\xae): data from an observational, longitudinal study

BackgroundTo evaluate the impact of treatment with recombinant human growth hormone (rhGH; Omnitrope®) on the risk of diabetes mellitus in adults with growth hormone deficiency (GHD), using data from the ongoing PATRO Adults post-marketing surveillance study.MethodsPATRO Adults is an ongoing post-marketing surveillance study being conducted in hospitals and specialized endocrinology clinics across Europe. All enrolled patients who receive ≥1 dose of Omnitrope® are included in the safety population. Patient profiles, containing all available study database information for each specific patient, were generated for all patients with adverse events (AEs) of diabetes mellitus while participating in the study. Diabetes mellitus was confirmed if fasting plasma glucose was ≥7.0 mmol/L or 2-h plasma glucose ≥11.1 mmol/L during oral glucose tolerance test or glycated hemoglobin ≥6.5%.ResultsUp to July 2018, 1293 patients had been enrolled in the study, and 983 (76.0%) remained active. Just under half (n = 687, 49.3%) of the patients were growth hormone (GH) treatment-naïve on entering the study, and most (n = 1128, 87.2%) had multiple pituitary hormone deficiency (MPHD). Diabetes mellitus/inadequate control (worsening) of diabetes mellitus was reported in 21 patients (22 events). The cases were newly diagnosed in 15 patients (age 29–84 years; incidence rate 3.61 per 1000 patient-years) and occurred in 6 patients with pre-existing diabetes mellitus at baseline (age 45–72 years). Most cases of newly diagnosed diabetes mellitus occurred in patients with adult-onset MPHD (n = 13); the remaining cases of new-onset diabetes mellitus occurred in a patient with childhood-onset MPHD who had previously received GH replacement therapy (n = 1), and a patient with adulthood-onset isolated GHD who was naïve to GH replacement therapy (n = 1). All cases of inadequate control/worsening of diabetes mellitus occurred in patients with adult-onset MPHD.ConclusionsBased on this snapshot of data from PATRO Adults, Omnitrope® treatment is tolerated in adult patients with GHD in a real-life clinical practice setting. No signals of an increased risk for diabetes mellitus have been noted so far, although continued follow-up (both during and after rhGH therapy) is required to confirm this.Trial registrationNot applicable.

Safety and effectiveness of empagliflozin in Japanese patients with type 2 diabetes: interim analysis from a post-marketing surveillance study

ABSTRACTBackground: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective treatments for type 2 diabetes mellitus (T2DM). We present the interim findings of an ongoing post-marketing surveillance (PMS) study in Japanese patients with T2DM receiving empagliflozin.Research design and methods: This 3-year, prospective, observational, multicenter PMS evaluated the safety and effectiveness of empagliflozin in Japanese clinical practice. Patients with T2DM who had not been treated with empagliflozin before enrollment were eligible. Assessments, including the primary endpoint of incidence of adverse drug reactions (ADRs), were based on electronic case report forms (eCRF).Results: Of 8,180 registered patients from 1,103 sites, 7,618 patients had an eCRF including a follow-up visit and were treated (mean age, 58.8 years; 10.5% aged ≥75 years; 63.2% male; mean HbA1c, 8.01%; 41.8% with HbA1c ≥8.0%; 24.8% and 61.8% with at least mild hepatic and renal impairment, respectively). Mean treatment duration was 98.4 weeks; 644 (8.5%) patients had ≥1 ADR, including 8.5% of patients aged ≥75 years. Hypoglycemia, urinary tract infection, genital infections, volume depletion, diabetic ketoacidosis, and lower limb amputation occurred in 0.28%, 0.62%, 0.53%, 0.33%, 0%, and 0.03% of patients, respectively.Conclusions: The reported ADRs were consistent with the known safety profile of empagliflozin.Trial registration: ClinicalTrials.gov identifier: NCT02489942.

Safety and effectiveness of ipragliflozin in elderly versus non-elderly Japanese type 2 diabetes mellitus patients: 12 month interim results of the STELLA-LONG TERM study

Objective: STELLA-LONG TERM is an ongoing post-marketing surveillance study examining the safety and effectiveness of ipragliflozin in real-world clinical practice in Japan. This interim report of STELLA-LONG TERM examined the safety and effectiveness of ipragliflozin in non-elderly and elderly Japanese patients with type 2 diabetes mellitus (T2DM) using data up to 12 months.Methods: Data from T2DM patients who were first prescribed ipragliflozin between July 2014 and October 2015 and whose 12 month data were locked by January 2018 were analyzed and compared between non-elderly (<65 years) and elderly patients (≥65 years).Results: The safety and efficacy analysis sets included 11,051 and 8788 patients, respectively. Elderly patients accounted for 28.6% (n = 3157) of the study population. The mean body mass index was 29.9 kg/m2 and 26.8 kg/m2, the percentage of patients with glycated hemoglobin (HbA1c) <8.0% was 50.1% and 59.5%, and the percentage of patients with complications was 83.2% and 87.3% in the non-elderly and elderly groups, respectively. Mean HbA1c and body weight decreased significantly from baseline to 12 months in both age groups, regardless of baseline HbA1c and body weight (all p < .05). The incidence of adverse drug reactions (ADRs) was 14.8% and 14.2% and that of serious ADRs was 0.8% and 1.4% in non-elderly and elderly patients, respectively (p = .002 for serious ADRs).Conclusion: The incidence of serious ADRs was higher in elderly patients than non-elderly patients. Ipragliflozin was effective in both non-elderly and elderly patients with T2DM in the real-world clinical setting.

Postmarketing surveillance on clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA-AF-Japan): Three-month interim analysis results.

BackgroundDirect oral anticoagulants are the first‐line drugs for anticoagulation therapy in nonvalvular atrial fibrillation (NVAF). However, a real‐world, large‐scale, clinical study on edoxaban has not been performed. Our ongoing postmarketing surveillance, ETNA‐AF‐Japan (Edoxaban Treatment in routiNe clinical prActice in patients with non‐valvular Atrial Fibrillation; UMIN000017011), was designed to collect such data.MethodsEnrollment started on 13 April 2015 and ended on 30 September 2017. Eligible patients were those diagnosed with NVAF who were to receive edoxaban for the first time and provided written consent for study participation. Baseline patient characteristics and adverse events (AEs) were collected.ResultsA total of 11 569 patients were enrolled. Data for 8157 patients in the first 3 months were analyzed. Mean age, body weight, creatinine clearance (CLcr), and CHADS 2 score were 74.2 ± 10.0 years, 60.0 ± 12.6 kg, 64.0 ± 25.6 mL/min, and 2.2 ± 1.3, respectively. Female patients, and patients with age ≥75 years, body weight ≤60 kg, and CLcr <30 mL/min constituted 40.7%, 52.4%, 54.6%, and 4.7%, respectively. Patients with paroxysmal, persistent, and permanent AF constituted 46.1%, 38.7%, and 15.1%, respectively. Most patients (85.3%) received dosages according to the prescribing information, and 90.8% continued the medication for 3 months. Bleeding AEs occurred in 3.29%, including major bleeding in 0.29%.ConclusionsThe majority (90.8%) of patients continued medication and no significant safety concerns related to edoxaban were reported during the first 3 months of treatment. Clearer safety and efficacy profiles of edoxaban await data analyses after the 2‐year follow‐up period.

RotaTeq™: a three-dose oral pentavalent reassortant rotavirus vaccine

Rotavirus (RV) is a leading cause of diarrhea worldwide, and will infect every child by their 5th birthday. The 3-dose oral pentavalent RV vaccine (RotaTeq™), consisting of serotypes G1, G2, G3, G4 and P1A[8], was licensed in the USA in 2006. The first dose should be administered between the ages of 6 and 12 weeks and the third dose should be given before the age of 32 weeks (USA) or 26 weeks (Europe). In a large clinical trial, the vaccine prevented 74% of cases of RV gastroenteritis, and 98% of cases of severe RV gastroenteritis (based on a symptomatology scoring scale) in the first rotavirus season. Vaccine efficacy in the second season was 62.6% against any RV gastroenteritis and 88% against severe disease. Vaccine efficacy in reducing hospitalizations and emergency department visits was 94.5% up to 2 years after vaccination. Results from a large clinical trial, as well as ongoing postmarketing surveillance, indicate that the vaccine is safe and well tolerated, without evidence of increased risk of intussusception. Further research is needed to establish vaccine efficacy in developing countries, particularly in Africa and Asia. Dissemination efforts should focus on ensuring the vaccine reaches the poorest children in whom disease morbidity and mortality is the highest.

Rotavirus Vaccine and Intussusception

On February 13, 2007, the Food and Drug Administration (FDA) released a public health notification on RotaTeq (Live, Oral, Pentavalent Vaccine—Merck and Co.) and intussusception.1 The report stated that there were 28 cases of intussusception in the ongoing post-marketing surveillance. Also, this notification stated that the purpose of this notification was to encourage the reporting of additional cases and to remind providers that “intussusception is a