Post-marketing Surveillance Study Research Articles

Long-Term Safety and Clinical Outcomes with Insulin Degludec/Insulin Aspart Treatment in Japanese Patients with Diabetes: A Real-World, Prospective, Observational Study

IntroductionInsulin degludec/insulin aspart (IDegAsp) provides effective glycaemic control with an acceptable safety profile in Japanese patients with diabetes in randomised clinical trials. This post-marketing surveillance study assessed long-term safety and clinical outcomes with IDegAsp in a Japanese real-world setting.MethodsMulticentre, prospective, observational, open-label, single-arm study of Japanese patients with diabetes requiring insulin therapy, who had switched to IDegAsp at their treating physician’s discretion in clinical practice. One year after initiating IDegAsp, incidence of adverse events (AEs [primary endpoint]), serious AEs, adverse drug reactions (ADRs), and severe hypoglycaemia (secondary safety endpoints) were assessed in the safety analysis set (SAS). Secondary effectiveness endpoints were change from baseline in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) in the effectiveness analysis set (EAS).ResultsOverall, 1321 patients were included (SAS, n = 1321; EAS, n = 1285); 4.2% with type 1 diabetes, 95.2% with type 2 diabetes, 0.7% with other/unknown diabetes type. In total, 204 AEs were reported in 132 patients (10.0% of the SAS), at a rate [95% confidence interval (CI)] of 16.2 events/100 patient-years of exposure (PYE) [14.0; 18.4]. By preferred term, ‘hypoglycaemia’ was the most frequent AE (45 events in 31 patients [2.3%]; rate [95% CI] 3.6 events/100 PYE [2.5; 4.6]). Serious AEs occurred in 4.2% of patients (rate [95% CI] 5.7 events/100 PYE [4.4; 7.0]), and ADRs in 3.1% (rate [95% CI] 4.6 reactions/100 PYE [3.4; 5.8]). Six events of severe hypoglycaemia were reported in five patients (0.4%; rate [95% CI] 0.5 events/100 PYE [0.1; 0.9]). Change from baseline to 1 year was − 0.51% and − 32.1 mg/dL for HbA1c and FPG, respectively (P < 0.0001 for both).ConclusionIn Japanese patients with diabetes, initiation of IDegAsp in real-world clinical practice was well tolerated, with no new safety signals, and associated with improved glycaemic control after 1 year. Trial RegistrationClinicalTrials.gov identifier, NCT02821052.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01978-2.

Safety Profile of Oxaliplatin in 3,687 Patients With Cancer in China: A Post-Marketing Surveillance Study.

BackgroundOxaliplatin (OXA), a third-generation platinum derivative, has become one of the main chemotherapeutic drugs for colorectal cancer and other cancers, but reports of adverse reactions are also increasing with the extensive application of OXA. In this study, post-marketing surveillance was carried out to investigate the safety profile of OXA in a real-world setting in Chinese cancer patients to provide a reference for the rational application of OXA.MethodsAll patients with cancer who received OXA-based chemotherapy in 10 tertiary hospitals in Hubei Province, China, between May 2016 and November 2016 were enrolled. A central registration method was used to document patients’ demographics, clinical use, and any incidence of adverse reactions to OXA. All adverse drug reactions (ADRs) were collected and analyzed to assess causality, severity, treatment, and outcome.ResultsIn total, 3687 patients were enrolled in this study. Approximately 64.6% of the patients were male, and 68.8% were aged 50-70 years, with a mean age of 55.3 years. The proportions of patients diagnosed with colorectal and gastric cancers were 59.3% and 31.6%, respectively. In this study, the overall incidence of ADRs and serious ADRs was 42.7% and 1.3%, respectively. The most common ADRs were gastrointestinal disorders (25.7%), blood disorders (21.1%), and peripheral nervous system disorders (8.0%). The serious ADRs identified were hypersensitivity reactions, thrombocytopenia, abnormal hepatic function, and leukopenia/neutropenia. The median onset of gastrointestinal toxicity, myelosuppression, peripheral neurotoxicity, and abnormal hepatic function was 1 d, 5 d, 1 d, and 14 d, respectively. The majority (84.7%) of hypersensitivity reactions were mild to moderate, and the median time to onset of these reactions was within the first 20 min of OXA infusion. Almost 88.0% of patients who experienced ADRs recovered or improved with treatment.ConclusionOur data suggest that OXA-induced ADRs are very common in Chinese patients with cancer; however, more attention should be paid to hypersensitivity reactions caused by OXA. This study provides a valuable reference regarding the safe application of OXA in a real-world setting.

Long-term safety and effectiveness of mycophenolate mofetil in adults with lupus nephritis: a real-world study in Japan.

To assess the safety and effectiveness of mycophenolate mofetil (MMF) in Japanese adults with lupus nephritis (LN) in real-world clinical practice. This multicentre, prospective, post-marketing surveillance study investigated the effectiveness and safety of MMF, as induction or maintenance therapy, in LN patients. Primary endpoints were adverse drug reactions (ADRs), changes in renal function from baseline, and relapse rate (RR) after 6 months in the maintenance group, estimated using the Kaplan-Meier method. Complete remission (CR) and partial remission (PR) were estimated by renal measurements. Overall, 112 patients were enrolled in the induction group and 340 in the maintenance group. Of these 452 patients, 418 were evaluable for safety and 396 for effectiveness. Eighty-three patients (19.85%) experienced ADRs, most commonly herpes zoster (3.34%) and diarrhoea (3.11%). Serious ADRs occurring in more than three patients were cytomegalovirus infections (1.43%), acute pyelonephritis (0.71%), and herpes zoster (0.71%). One patient died from herpes zoster disseminated. CR and PR were 19.54% and 44.82%, respectively, in the induction group, and 40.62% and 66.16%, respectively, in the maintenance group. RR in the maintenance group was 0.70%. The tolerability of MMF is in line with that reported in other studies. Since the average dose of MMF was <1.5 g/day, research into the optimal dose for achieving effectiveness is required.

Safety of Tacrolimus in Autoimmune Disease: Results From Post-marketing Surveillance in South Korea.

Tacrolimus, a macrolide immunosuppressant, is approved in Korea for the treatment of rheumatoid arthritis (RA), lupus nephritis (LN) and myasthenia gravis (MG) We report three prospective post-marketing surveillance studies of tacrolimus conducted in South Korea in these indications. Studies were conducted according to South Korean Ministry of Food and Drug Safety requirements Patients were followed up for the duration of the study (up to 4 years) or until treatment discontinuation Occurrence and likely relationship with tacrolimus of adverse events (AEs), adverse drug reactions (ADRs; defined as AEs where causal relationship to tacrolimus could not be excluded) and serious AEs were recorded Association of AEs with demographic and medical factors was evaluated by multivariable analysis. The studies included 740 (RA), 307 (LN) and 104 (MG) patients The incidence of AEs was 127% in RA (642% of AEs potentially related to tacrolimus), 209% (378% potentially related) in LN and 298% (568% potentially related) in MG The incidence of ADRs was 84%, 98% and 202%, respectively Serious AEs were reported in 07%, 72% and 87%, respectively The most common AEs were abdominal pain (RA), pharyngitis (LN) and diarrhea (MG) Unexpected AEs occurred in 35% of patients with RA, 29% in LN and 87% in MG; no pattern of unexpected AEs was apparent Multivariable analysis demonstrated that patients with comorbidity had higher probability of experiencing an AE in RA and MG studies. The incidence of AEs and the safety profile of tacrolimus in each indication was consistent with previous reports.

Real-world safety and effectiveness of nivolumab in Japanese patients with unresectable advanced or recurrent gastric/gastroesophageal junction cancer that has progressed after chemotherapy: a postmarketing surveillance study

BackgroundThis postmarketing surveillance study evaluated the real-world safety and effectiveness of nivolumab as salvage (after ≥ 2 lines) therapy in Japanese patients with unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer.MethodsThis multicenter, observational study was conducted at 158 centers in Japan. Patients with unresectable advanced or recurrent G/GEJ cancer were registered between Nov 1, 2017, and Oct 31, 2018, and observed for 6 months after treatment initiation with nivolumab. Correlation of background characteristics with treatment-related adverse events (TRAEs) and tumor response was explored.ResultsOverall, 654 patients were registered (safety analysis set, n = 650; effectiveness analysis set, n = 636; response evaluation set, n = 516). The incidences of all TRAEs and grade ≥ 3 TRAEs were 31.5 and 11.2%, respectively. TRAEs significantly correlated with the absence of peritoneal metastasis; C-reactive protein level < 1; prior G/GEJ cancer surgery; and past or concomitant pulmonary, thyroid, or renal disease (each p < 0.05). The incidence of TRAEs was significantly lower in patients with higher Glasgow prognostic scores (p < 0.05). No new safety signals were observed. Complete response, partial response, stable disease, and progressive disease were observed in 1.2, 10.1, 27.1, and 58.3% of the response evaluation set, respectively. Patients aged ≥ 65 years (13.9 vs 5.3%, p = 0.0083) and ≥ 75 years (18.8 vs 9.2%, p = 0.0036) showed a higher response rate than their younger counterparts.ConclusionsThe real-world safety and effectiveness of nivolumab as salvage (after ≥ 2 lines) therapy in Japanese patients with unresectable advanced or recurrent G/GEJ cancer were consistent with those observed in the phase 3 ATTRACTION-2 study.

Real-world safety and efficacy of CT-P13, an infliximab biosimilar, in Japanese rheumatoid arthritis patients naïve to or switched from biologics.

The aim of this post-marketing surveillance (PMS) study is to evaluate the real-world safety and efficacy of CT-P13, the first biosimilar of infliximab (IFX). Japanese patients with rheumatoid arthritis were prospectively registered from November 2014 and followed up for 1 year. Of 794 patients in the analysis set, 318 patients naïve to biological disease-modifying antirheumatic drugs (bDMARDs) showed an immediate decrease in Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) and increased remission rate (DAS28-CRP < 2.6). In patients who switched from IFX to CT-P13 for non-medical reasons (n = 374), the low DAS28-CRP due to previous IFX treatment decreased further with continued CT-P13 therapy. As in naïve patients, patients who switched from other bDMARDs, mainly for medical reasons (n = 102), responded similarly to CT-P13. CT-P13 in this PMS and IFX in a previous PMS had similar adverse reaction profiles, although the incidence rate in naïve patients in this current PMS was lower due to earlier initiation of CT-P13 therapy. CT-P13 showed excellent effectiveness as first-line therapy, no clinical difficulties in switching from IFX, and clinical improvement in patients who failed other bDMARDs. CT-P13 could be a cost-effective alternative to IFX in the treatment of rheumatoid arthritis.

Safety and Effectiveness of Plerixafor for Peripheral Blood Stem Cell Mobilization in Autologous Stem Cell Transplantation: Results of a Post-Marketing Surveillance Study

BackgroundPlerixafor was approved in Japan in 2016 for peripheral blood stem cell (PBSC) mobilization in autologous stem cell transplantation (A-SCT).ObjectiveOur objective was to evaluate the safety and effectiveness of plerixafor in Japanese patients undergoing A-SCT for various indications in real-world practice.Patients and MethodsThis post-marketing surveillance study included Japanese patients initiating PBSC mobilization with plerixafor for A-SCT. Safety assessments included the incidence of adverse events (AEs) including serious AEs, adverse drug reactions (ADRs), and laboratory variables. Effectiveness assessments were the proportion of patients with the target CD34+ cell yield (≥2 × 106 cells/kg) ≤4 days after plerixafor administration and the number of days required to reach the target CD34+ cell yield.ResultsIn total, 785 patients were registered, and the safety and effectiveness analysis sets comprised 764 and 717 patients, respectively. ADRs occurred in 12.2% of patients, with gastrointestinal disorders (5.5%), laboratory investigations (4.5%), and blood and lymphatic system disorders (3.0%) being the most common. A total of 71.1% of patients had the target CD34+ cell yield within ≤4 days of treatment, with a mean (standard deviation) of 1.3 (0.7) days to reach the target CD34+ cell yield. Over 80% of patients with a baseline CD34+ cell count >2 cells/μL had a target CD34+ cell yield within ≤4 days of treatment.ConclusionsThis large post-marketing surveillance study provided real-world evidence detailing the safety and effectiveness of plerixafor for PBSC mobilization in Japanese patients undergoing A-SCT. Importantly, no new safety concerns were identified, and the safety profile of plerixafor was consistent with the established profile of this drug.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00276-1.

A Modular Approach to Combine Postmarket Clinical Follow-Up Studies and Postmarket Surveillance Studies

The European Medical Device Regulation 2017/745 (MDR) has its date of application in May 2021. This new legislation has refined and expanded the need of manufacturers to have a postmarket surveillance (PMS) system. According to this legislation, a postmarket clinical follow-up (PMCF) plan is also required. Manufacturers of high-risk medical devices are obliged to conduct both PMCF and PMS studies. There is thus the need to generate evidence from clinical data. The conduct of several studies for PMS and PMCF can be cumbersome. We therefore aim to present a modular approach to combine PMS and PMCF studies into a single study. We extracted the topics listed in the MDR, especially Annex XV, Section 3, the Good Clinical Practice for medical devices (EN 14155:2020, Annex A). In addition, we added topics according to the SPIRIT and the SPIRIT-PRO statement and created a draft clinical investigation plan (CIP). The CIP template is provided as part of the manuscript. The modular concept has passed the required regulatory and legal requirements for one specific study. A modular approach for combining PMCF and PMS studies in a single CIP has been developed and implemented, and it is ready for use. The provided CIP template should enable other researchers and groups to adopt this concept according to their needs.

Long-Term Safety and Effectiveness of Thyrotropin Alfa in Japanese Patients: A Post-Marketing Surveillance Study.

IntroductionReal-world evidence of the safety and effectiveness of recombinant human thyroid-stimulating hormone (rhTSH; thyrotropin alfa) in Japanese patients is lacking.MethodsThis was a post-marketing surveillance study that included all Japanese patients who received thyrotropin alfa, either as a supporting diagnostic from January 2009 to December 2016, or as adjunctive treatment for ablation from May 2012 to October 2018. Information was collected on patient demographics, thyroid cancer characteristics, adverse drug reactions (ADRs), scintigraphy, serum thyroglobulin (Tg) testing, and hypothyroidism symptoms.ResultsA total of 9268 patients were included in the safety analysis and 9031 in the effectiveness analysis. In the safety analysis set, 3444 patients received thyrotropin alfa as a diagnostic and 5822 received it as treatment. ADRs occurred in 7.1% (n = 660) of patients, including 9.4% (n = 324) of patients who received thyrotropin alfa as a diagnostic and 5.8% (n = 336) of patients who received it as treatment. Nausea was the most common ADR (4.0% of overall safety population). Among patients who received thyrotropin alfa as a diagnostic (n = 1835), the Tg test was positive in 53.6% after the second dose. The scintigram was rated as “readable” in 3023 of the 3054 patients included in this analysis (99.0%). Of the 765 patients who were included in the assessment of response to ablation at 6 months to 1 year after the procedure, 621 (81.2%) were considered to have had “treatment success”. There were no significant differences in the proportions of patients who had hypothyroidism symptoms before the first and after the second dose of thyrotropin alfa.ConclusionIn this large post-marketing surveillance study, thyrotropin alfa was well tolerated and showed effectiveness that was comparable to that observed in randomised, controlled trials.

Dexamethasone Intravitreal Implant for the Treatment of Macular Edema Following Retinal Vein Occlusion: Post Hoc Analysis of Post-Marketing Surveillance Data in the Real-World Setting in Korea.

PurposeTo supplement established efficacy and safety data, this analysis evaluated the real-world use of dexamethasone (DEX) intravitreal implant 700 µg for retinal vein occlusion (RVO)-related macular edema in an Asian population and baseline factors potentially associated with DEX implant efficacy.Patients and MethodsA prospective, observational, post-marketing surveillance study was conducted at 38 sites in South Korea in patients consecutively presenting with macular edema following branch or central RVO (BRVO, CRVO), and administered a first DEX implant. Follow-up visits and subsequent DEX or other therapies conformed with local practice. Outcome measures included best-corrected visual acuity (BCVA), change in BCVA from baseline, responder rates, and adverse events. Associations between baseline characteristics and BCVA gains were evaluated. Month-1, -2, -4, and -6 visit analysis windows were established.ResultsIn all, 700 patients (79.1% BRVO, 20.9% CRVO) received 1.12 DEX implants (mean) and were followed for 101.5 days (standard deviation, 51.7); 90% received a single implant. Among patients with analyzable data, mean BCVA improved from baseline with peak changes in Month 2 of −0.193 and −0.212 LogMAR, (P < 0.0001) and remained significant in the BRVO subgroup at the Month 4 and 6 windows (P < 0.0001 and P = 0.0039, respectively). Treatment-naïve patients experienced greater BCVA increases. The proportion of patients with stable/improved BCVA tended to decrease after Month 2 through Month 6 and the decline was greater in the CRVO subgroup. At the Month-2 window, ≥1-, 2- and 3-line increases were positively associated with younger age, worse baseline BCVA, and treatment naivety. The most common adverse event was increased intraocular pressure.ConclusionIn the real-world clinical setting in South Korea, DEX implant improved visual acuity and had a favorable safety profile similar to that reported in randomized controlled trials and observational European and North American studies. These data further support the value of DEX implant as a treatment option for RVO.ClinicalTrials.gov IdentifierNCT01976650. Date of registration: November 6, 2013.

Real-World Outcomes of Intravitreal Aflibercept for Neovascular Age-Related Macular Degeneration: A Large-Scale Postmarketing Surveillance in Korea.

PurposeTo investigate the efficacy and safety of intravitreal aflibercept (IVT-AFL) in Asian patients with neovascular age-related macular degeneration (nAMD) in a real-world clinical setting.Patients and MethodsIn this analysis of a prospective, regulatory, postmarketing surveillance study for IVT-AFL, 3115 patients with nAMD were included and followed for 8 months. The mean changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were analyzed using last observation carried forward method. A post hoc subgroup analysis and a multivariate logistic regression analysis were also performed to assess factors related to treatment outcomes.ResultsMean BCVA improved from 0.62 to 0.51 logarithm of minimum angle resolution and mean CRT decreased from 383.3 to 289.7 μm, with a mean of 3.4 injections during the 8-month follow-up. In the subgroup analysis, patients who had received 3 initial monthly doses had significantly better anatomical improvements than those treated as needed. Patients with confirmed polypoidal choroidal vasculopathy (PCV) had significantly better anatomical improvements and better visual recovery than those with other types of nAMD. The multivariate regression analysis demonstrated that age, injection number, PCV, and baseline BCVA were significantly associated with higher odds of gaining 3 lines at 8 months, and sex, injection number, PCV, and baseline CRT were associated with CRT ≤250 µm at 8 months. No new safety findings were identified.ConclusionIVT-AFL was effective and well tolerated in a real-world setting with a large number of Asian patients with nAMD. Number of injections and PCV were important determinants for improved treatment outcomes.

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.

Post-Marketing Surveillance Study to Substantiate the Efficacy and Safety for the Combination of Paracetamol, Phenylephrine, Chlorpheniramine Maleate, Sodium Citrate and Menthol in Indian Patients of Common Cold

Introduction: Common cold is frequently encountered by people and it also largely affects productivity of the daily routine life. Combination of Paracetamol, Phenylephrine and Chlorpheniramine maleate which acts as an antipyretic, nasal decongestant and anti-histaminic respectively, can be used for the symptomatic treatment of common cold. To the above-mentioned combination, Sodium Citrate was added as an expectorant and Menthol for cooling effect and this post marketing surveillance study was conducted to test the efficacy and safety for the symptomatic treatment of common cold. Methodology: Out of 200 enrolled, 174 patients completed the study. Safety assessment was made by analysing the adverse events reported by the patient or their guardian. Efficacy was evaluated by total symptom score [TSS] (eleven-point scale ranging from 0 to 10 where 0 is no symptom to 10 is the maximum symptoms) which was extrapolated to four-point Likert-type symptom severity scales. Results: TSS was reduced from 5.57 at baseline visit to 3.40 at day 3 to 1.69 at day 5. At day 3 and day 5 there was TSS reduction of 38.865 % and 69.690 % respectively as compared to baseline. 18 episodes of adverse drug reactions were reported and all of them were of expected and non-serious nature. Conclusion: Fixed-dose combination of Paracetamol 125mg, Phenylephrine 5mg, Chlorpheniramine Maleate 1mg, Sodium Citrate 60mg and mentholated flavoured syrupy base q.s. per 5ml was found to be safe and efficacious for the treatment of common cold in children of age between 2 to 12 years.

Efficacy and Safety for the Combination of Neomycin, Beclomethasone, Clotrimazole and Lignocaine for the Treatment of Otitis Media with Perforation and Otitis Externa: Post-Marketing Surveillance Study

Introduction: Bacterial and/ or fungal infection of the middle or external ear can be painful and sometimes the infection can be of mixed nature i.e. caused due to both bacteria and fungi. The combination of antibiotics and antifungals can be used for the treatment of mixed ear infections, along with it, anti-inflammatory agent and anaesthetics can be combined to relieve the discomfort caused by the infection. This study was conducted to test the efficacy and safety for the combination of Neomycin, Beclomethasone, Clotrimazole and Lignocaine for the treatment of middle or external ear infection.&#x0D; Method: Of enrolled 200, 177 patients completed the study. Efficacy was evaluated by symptom score (SS) scale which was an eleven-point scale ranging from 0 to 10 where 0 was no symptom to 10 was the maximum tolerated symptoms. All patients were asked to report SS on SS scale for ear pain, ear discharge and ear itching on day 1, 3 and 5. Safety assessment was made by analysing the adverse events reported by the patient.&#x0D; Results: SS of ear pain was reduced from 6.158 at baseline visit to 3.050 at day 3 to 0.468 at day 5. SS of ear discharge reduced from 6.175 at baseline to 2.768 at day 3 to 0.491 at day 5. SS of ear itching reduced from 4.694 at baseline to 1.604 at day 3 to 0.299 at day 5.&#x0D; Conclusion: The investigational product was found to be efficacious and safe for the treatment of otitis media and externa.&#x0D;

Efficacy and Safety of SATAKE HotBalloon® Catheter for Treatment of Paroxysmal Atrial Fibrillation - A Post-Marketing Surveillance Study.

SATAKE HotBalloon®catheter (HBC) is a radiofrequency balloon catheter for the treatment of atrial fibrillation (AF), and was approved for use in Japan to treat drug-resistant paroxysmal AF in 2015. Post-marketing surveillance study was conducted by Toray Industries, Inc. to evaluate the efficacy and safety of HBC treatment in patients with paroxysmal AF in a real-world setting. This study is the first nation-wide survey of HBC treatment for paroxysmal AF in clinical practice in Japan.Methods and Results:This was a single-arm, multicenter observational study with an observation period of 48 weeks after ablation. Pulmonary vein isolation and AF non-recurrence rates were evaluated and adverse events (AEs) were observed at 46 sites in Japan. An AF event was defined as recurrence of AF or re-ablation from 12 to 48 weeks after ablation. The success rate of pulmonary vein isolation was 99.0% (486/491) for patients with AF. The cumulative AF non-recurrence rate was 94.1% at 24 weeks and 87.8% at 48 weeks. AEs were found to occur 21.5% (114/530), and ablation-related AEs were found to occur 2.6% (14/530) during the study period, with the most common being pericardial effusion (0.8%, 4/530). This study demonstrates the efficacy and safety of HBC ablation in Japanese patients with recurrent symptomatic paroxysmal AF refractory to antiarrhythmic therapy.

Safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus and impaired renal function: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM)

STELLA-LONG TERM, a 3-year post-marketing surveillance study, evaluated the safety and effectiveness of the sodiumglucose cotransporter 2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients. Final results in the safety (n = 6697) and effectiveness populations (n = 5625) were analyzed by stratifying patients by baseline estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) into four subgroups (≥90, 60 to &lt;90, 45 to &lt;60, and &lt;45) and two subgroups (≥60 and &lt;60). Adverse drug reaction (ADR) incidence, and changes from baseline in glycosylated hemoglobin (HbA1c), bodyweight, and eGFR were assessed. The percentage of patients experiencing ADRs and serious ADRs was similar across most eGFR subgroups. Polyuria/pollakiuria was the most common ADR. Renal disorders and volume depletion ADRs were more frequent in the subgroups with more severe renal impairment at baseline than in those with an eGFR of 60 to &lt;90 or ≥90 mL/min/1.73 m2. Bodyweight and HbA1c decreased in all subgroups, the latter by − 0.91% to − 0.40% (P &lt;0.05 vs. baseline). eGFR increased in the 45 to &lt;60 mL/min/1.73 m2 subgroup (+ 1.42 ± 8.77 mL/min/1.73 m2; P = 0.006). It decreased in the ≥90 and 60 to &lt;90 mL/min/1.73 m2 subgroups (− 8.27 ± 13.73 and − 1.22 ± 10.34 mL/min/1.73 m2; P &lt;0.001), but not to &lt;60 mL/min/1.73 m2. In conclusion, there were no new or unexpected safety findings in Japanese patients treated with ipragliflozin for T2DM, and long-term sustained improvements in HbA1c and bodyweight were observed regardless of the presence of renal impairment.

A multi-centre, post-marketing surveillance study of Vi polysaccharide–tetanus toxoid conjugate vaccine (Typbar TCV®) in India

ABSTRACT A typhoid Vi capsular-polysaccharide tetanus toxoid conjugate vaccine (Typbar-TCV®) was recommended by the World Health Organization for use in children >6 months of age. The present post-marketing surveillance study was intended to assess the clinical safety of approximately 11 million doses of TCV sold till 2019 in a diverse age range Indian population. Both active and passive post-marketing surveillance studies were conducted at multiple centers. Active surveillance was performed in two periods, Period-I: February to October 2016, Period-II: April 2017 to October 2018. In Period-II, the Brighton Collaboration Criteria adverse event case definitions were used. Passive surveillance was performed from February 2016 to December 2019 through voluntary reporting by pediatricians across India. During the active surveillance, 1147 adverse events were reported among 4,991 (23.0%) subjects in Period-I, and 596 adverse events among 3898 (21.3%) subjects in Period-II. The most frequent adverse events were fever (9.2% and 12.02%in Periods I and II, respectively), pain at the injection site (8.3% and 7.33%), and swelling (4.0% and 1.93%). No serious adverse events (SAEs) were reported during either Period. Passive surveillance revealed 235 adverse events, including 25 SAEs requiring hospitalization, of which two were due to typhoid fever. All the events mentioned above occurred within one week of vaccination, and all the subjects have recovered from AEs with medications. All reported adverse events resolved with no clinical sequelae. Observations in this study are consistent with the pre-licensure studies with no additional safety signals detected, confirming that Typbar-TCV® is safe. Abbreviations: AE: Adverse event; LMIC: low- and middle-income countries; PMS: Post-marketing surveillance; SAE: Serious adverse event; TCV: Vi-polysaccharide tetanus –toxoid conjugate vaccine (Typbar-TCV®)

Safety and Effectiveness of Recombinant Human Growth Hormone in Children with Turner Syndrome: Data from the PATRO Children Study

Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). Methods: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7–18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was −2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of −2.02 (0.9). Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

EFFICACY AND SAFETY FOR THE COMBINATION OF PARACETAMOL, PHENYLEPHRINE AND CHLORPHENIRAMINE MALEATE IN INDIAN PAEDIATRIC PATIENTS OF COMMON COLD AND ALLERGIC RHINITIS- POST-MARKETING SURVEILLANCE STUDY

Introduction: Common cold is Self-recovering respiratory diseases which can be caused by viral infection. As till date there is no treatment for the common cold and it is self-limiting in nature, symptomatic treatment is the only option. Symptomatic treatment of common cold with a single drug is not efficacious as compared to the multiple drug combination. Combination of antipyretic (Paracetamol), nasal decongestant (Phenylephrine) and anti-histaminic agent (Chlorpheniramine Maleate) can be used for the symptomatic treatment of common cold. This post marketing surveillance study was conducted to test the efficacy and safety for the fixed dose combination of Paracetamol 125mg, Phenylephrine Hydrochloride 2.5mg and Chlorpheniramine Maleate 1mg per ml in Indian patients of age 1 to 12 months.&#x0D; Methodology: Out of 200 enrolled, 164 patients completed the study. Efficacy was evaluated by total symptom score (TSS) ranging from 0 to 10 where 0 was no symptom to 10 was the maximum tolerated symptoms. TSS was further extrapolated to four-point-Likert-type-symptom-severity-scale. Safety assessment was done by evaluation of adverse events reported by the patient.&#x0D; Results: TSS was reduced from 5.91 on day 1 to 3.57 on day 3 and 1.47 on day 5. At day 3 and day 5 the percentage reduction in the TSS as compared to the baseline was 39.48 and 75.05 respectively. During the study only 8 episodes of ADRs were reported including sedation and drowsiness.&#x0D; Conclusion: Combination of Paracetamol, Phenylephrine and Chlorpheniramine Maleate was found to be efficacious and safe for the treatment of common cold and allergic rhinitis.&#x0D; Keywords: Paracetamol, Phenylephrine, Chlorpheniramine Maleate, Common Cold, Allergic Rhinitis.

Elotuzumab Plus Lenalidomide/Dexamethasone (ELd) Vs Ld in Patients with Newly Diagnosed Multiple Myeloma: Phase 2, Randomized, Open-Label Study in Japan

Introduction: Elotuzumab, a humanized IgG1 monoclonal antibody that binds to SLAMF7 expressed on myeloma and natural killer (NK) cells, has a dual mode of action; it causes targeted myeloma cell death by directly activating NK cells and enhances NK cell-mediated antibody-dependent cellular cytotoxicity. Elotuzumab combined with lenalidomide and dexamethasone (ELd) has been approved in Japan for the treatment of relapsed/refractory multiple myeloma (RRMM). In a 4-y follow-up of the phase 3 ELOQUENT-2 study (NCT01239797) in patients (pts) with RRMM, ELd demonstrated a sustained 29% reduction in risk of disease progression/death and an overall survival benefit vs Ld (Dimopoulos M et al. Haematologica 2017), consistent with prior reports (Dimopoulos M et al. Br J Haematol 2017). We present the first report on the efficacy/safety of ELd vs Ld in pts with newly diagnosed multiple myeloma (NDMM).Methods: In this phase 2, open-label, multicenter study (NCT02272803) in Japan enrolling pts with NDMM ineligible for high-dose chemotherapy plus hematopoietic cell transplantation, pts were randomized 1:1 to intravenous elotuzumab (10 mg/kg weekly for Cycles 1 and 2; every 2 wk for Cycles 3-18; 20 mg/kg monthly thereafter) plus Ld or Ld alone, in a 28-d cycle until disease progression or unacceptable toxicity. All pts in the ELd arm received premedication prior to elotuzumab to mitigate infusion reactions (IRs). In the absence of IRs, infusion rate was increased from 0.5-2.0 mL/min at dose 1, and up to a maximum of 5 mL/min (per FDA/EMA labels for ELd in RRMM) by dose 3 of Cycle 1. Primary endpoint was investigator-assessed objective response rate (ORR) with ELd, per International Myeloma Working Group criteria (1-sided α=0.15 for a true response rate >71%). Secondary endpoints included difference in ORR between the arms and progression-free survival (PFS). Safety was an exploratory endpoint.Results: In total, 40 and 42 pts received ELd and Ld, respectively. At database lock (March 2017; minimum follow-up of 6 mo), 31 (78%) pts in the ELd arm and 25 (60%) in the Ld arm remained on study. At baseline, median (range) age was 72 y (65-83) in the ELd arm and 73 y (62-89) in the Ld arm. Median duration of therapy was 13.0 cycles with ELd and 11.5 cycles with Ld. The most common reason for discontinuation was: ELd (9 pts)-disease progression (4/40 pts [10%]); Ld (17 pts)-drug toxicity, adverse events (AEs) unrelated to study drug, and pt request (each with 4/42 pts [10%]). The primary endpoint was met: investigator-assessed ORR (Table) was 88% with ELd; lower bound of the 2-sided 70% CI in ORR was 80% (> threshold of 71%). The ORR in the LD arm was 74%. ORR was 13% numerically higher with ELd than Ld. Very good partial response or better was observed for 45% of ELd- and 29% of Ld-treated pts. AEs were reported in 40 (100%) and 41 (98%) pts in the ELd and Ld arms, respectively. The most common (≥20%) AEs for ELd vs Ld included constipation (43% vs 31%), pyrexia (35% vs 7%), rash (28% vs 36%), diarrhea (28% vs 21%), nasopharyngitis (25% vs 26%), dysgeusia (23% vs 19%), malaise (23% vs 2%), peripheral edema (20% vs 14%), neutropenia (20% vs 14%), leukopenia (20% vs 7%), and back pain (18% vs 21%). Grade (G) 3-4 AEs occurred in 31 (78%) and 19 (45%) pts in the ELd and Ld arms, respectively. The most common G3-4 AEs (ELd vs Ld) were neutropenia (18% vs 7%) and leukopenia (15% vs 0%). One IR was reported (ELd): G2 hypersensitivity during the first infusion (2-mL/min infusion rate); elotuzumab infusion was interrupted; the pt did not experience any IRs at subsequent infusions. Thirty-eight pts (95%) received elotuzumab at 5 mL/min (representing 1046/1176 [89%] infusions) and no IRs were reported at this increased infusion rate. Secondary primary malignancies were reported in 1 pt in each arm (of the rectum and lung with ELd and Ld, respectively). ELd had a comparable safety profile when given at 10 mg/kg weekly or every 2 wk up to Cycle 18, or at 20 mg/kg monthly from Cycle 19 onwards. PFS data are not yet mature.Conclusions: In this first report of ELd treatment of pts with NDMM, the primary endpoint of ORR was met. ELd had an acceptable safety profile in this pt population, and an increased infusion rate of 5 mL/min, which reduced infusion time and did not induce additional IRs. These data suggested that ELd with a faster infusion rate of 5 mL/min was effective and well tolerated in Japanese pts with NDMM.Study support: Bristol-Myers Squibb K.K. [Display omitted] DisclosuresOhta:Bristol-Meyer Squibb K.K., Celgene K.K., Jansen Pharmaceutical K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd: Honoraria. Hori:Celgene, Fujifilm RI Pharma, Shire Japan: Other: Post-marketing surveillance study fee. Kinoshita:Bristol-Myers Squibb K.K.: Employment. Shelat:Bristol-Myers Squibb: Employment, Equity Ownership. Miyoshi:Bristol-Myers Squibb K.K.: Employment.