scholarly journals Joint modelling of multivariate longitudinal clinical laboratory safety outcomes, concomitant medication and clinical adverse events: application to artemisinin-based treatment during pregnancy clinical trial

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Noel Patson ◽  
Mavuto Mukaka ◽  
Umberto D’Alessandro ◽  
Gertrude Chapotera ◽  
Victor Mwapasa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Alanine Aminotransferase ◽  
Concomitant Medication ◽  
Total Bilirubin ◽  
Safety Data ◽  
Poisson Model ◽  
Joint Model ◽  
Laboratory Safety ◽  
Joint Modelling ◽  
Safety Outcomes

Abstract Background In drug trials, clinical adverse events (AEs), concomitant medication and laboratory safety outcomes are repeatedly collected to support drug safety evidence. Despite the potential correlation of these outcomes, they are typically analysed separately, potentially leading to misinformation and inefficient estimates due to partial assessment of safety data. Using joint modelling, we investigated whether clinical AEs vary by treatment and how laboratory outcomes (alanine amino-transferase, total bilirubin) and concomitant medication are associated with clinical AEs over time following artemisinin-based antimalarial therapy. Methods We used data from a trial of artemisinin-based treatments for malaria during pregnancy that randomized 870 women to receive artemether–lumefantrine (AL), amodiaquine–artesunate (ASAQ) and dihydroartemisinin–piperaquine (DHAPQ). We fitted a joint model containing four sub-models from four outcomes: longitudinal sub-model for alanine aminotransferase, longitudinal sub-model for total bilirubin, Poisson sub-model for concomitant medication and Poisson sub-model for clinical AEs. Since the clinical AEs was our primary outcome, the longitudinal sub-models and concomitant medication sub-model were linked to the clinical AEs sub-model via current value and random effects association structures respectively. We fitted a conventional Poisson model for clinical AEs to assess if the effect of treatment on clinical AEs (i.e. incidence rate ratio (IRR)) estimates differed between the conventional Poisson and the joint models, where AL was reference treatment. Results Out of the 870 women, 564 (65%) experienced at least one AE. Using joint model, AEs were associated with the concomitant medication (log IRR 1.7487; 95% CI: 1.5471, 1.9503; p < 0.001) but not the total bilirubin (log IRR: -0.0288; 95% CI: − 0.5045, 0.4469; p = 0.906) and alanine aminotransferase (log IRR: 0.1153; 95% CI: − 0.0889, 0.3194; p = 0.269). The Poisson model underestimated the effects of treatment on AE incidence such that log IRR for ASAQ was 0.2118 (95% CI: 0.0082, 0.4154; p = 0.041) for joint model compared to 0.1838 (95% CI: 0.0574, 0.3102; p = 0.004) for Poisson model. Conclusion We demonstrated that although the AEs did not vary across the treatments, the joint model yielded efficient AE incidence estimates compared to the Poisson model. The joint model showed a positive relationship between the AEs and concomitant medication but not with laboratory outcomes. Trial registration ClinicalTrials.gov: NCT00852423

scholarly journals Joint modelling of multivariate longitudinal clinical laboratory safety outcomes, concomitant medication and clinical adverse events: Application to artemisinin-based treatment during pregnancy clinical trial

2021 ◽  
Author(s):  
Noel Patson ◽  
Mavuto Mukaka ◽  
Umberto D’Alessandro ◽  
Gertrude Chapotera ◽  
Victor Mwapasa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Alanine Aminotransferase ◽  
Concomitant Medication ◽  
Total Bilirubin ◽  
Safety Data ◽  
Poisson Model ◽  
Joint Model ◽  
Laboratory Safety ◽  
Joint Modelling ◽  
Safety Outcomes

Abstract Background In drug trials, clinical adverse events (AEs), concomitant medication and laboratory safety outcomes are repeatedly collected to support drug safety evidence. Despite the potential correlation of these outcomes, they are typically analysed separately, potentially leading to misinformation and inefficient estimates due to partial assessment of safety data. Using joint modelling, we investigated whether clinical AEs vary by treatment and how laboratory outcomes (alanine amino-transferase, total bilirubin) and concomitant medication are associated with clinical AEs over time following artemisinin-based antimalarial therapy. Methods We used data from a trial of artemisinin-based treatments for malaria during pregnancy that randomized 870 women to receive artemether–lumefantrine (AL), amodiaquine–artesunate (ASAQ) and dihydroartemisinin–piperaquine (DHAPQ). We fitted a joint model containing four sub-models from four outcomes: longitudinal sub-model for alanine aminotransferase, longitudinal sub-model for total bilirubin, Poisson sub-model for concomitant medication and Poisson sub-model for clinical AEs. Since the clinical AEs was our primary outcome, the longitudinal sub-models and concomitant medication sub-model were linked to the clinical AEs sub-model via current value and random effects association structures respectively. We fitted a conventional Poisson model for clinical AEs to assess if the effect of treatment on clinical AEs (i.e. incidence rate ratio (IRR)) estimates differed between the conventional Poisson and the joint models, where AL was reference treatment.Results Out of the 870 women, 564 (65%) experienced at least one AE. Using joint model, AEs were associated with the concomitant medication (log IRR 1.7487; 95% CI: 1.5471, 1.9503; p<0.001) but not the total bilirubin (log IRR: -0.0288; 95% CI: -0.5045, 0.4469; p=0.906) and alanine aminotransferase (log IRR: 0.1153; 95% CI: -0.0889, 0.3194; p=0.269). The Poisson model underestimated the effects of treatment on AE incidence such that log IRR for ASAQ was 0.2118 (95% CI: 0.0082, 0.4154; p=0.041) for joint model compared to 0.1838 (95% CI: 0.0574, 0.3102; p=0.004) for Poisson model.Conclusion We demonstrated that although the AEs did not vary across the treatments, the joint model yielded efficient AE incidence estimates compared to the Poisson model. The joint model showed a positive relationship between the AEs and concomitant medication but not with laboratory outcomes. Trial registration ClinicalTrials.gov: NCT00852423.

Systemic Antifungal Drugs in the Hematology and Oncology Setting: A Real-Life Analysis in Consecutive Leukemia Patients of Patterns of Usage and Associated Problems,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4198-4198
Author(s):  
Barbara Metzke ◽  
Stefanie Hieke ◽  
Manfred Jung ◽  
Ralph Waesch ◽  
Monika Engelhardt
Keyword(s):  
Adverse Events ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Research Funding ◽  
Concomitant Medication ◽  
Total Bilirubin ◽  
Real Life ◽  
Antifungal Prophylaxis ◽  
Antifungal Drugs ◽  
Liposomal Amphotericin B

Abstract Abstract 4198 Introduction: Invasive fungal infections (IFI) show high morbidity and mortality rates in immunocompromised patients (pts). Systemic antifungal drugs (SAD), therefore, play an important role in the supportive care, especially in patients with acute leukemia. Over the last few years, new drugs for the prevention and treatment of IFI have been introduced. Due to the difficult diagnostics of IFI, SAD are broadly used, which represents a substantial burden for public health systems and raises issues about the optimal antifungal regimen as well as drug safety. Apart from their high costs, the use of these drugs is hampered by potential drug interactions and adverse events. We determined the extent of SAD use as well as frequency and clinical relevance of problems related to these drugs in a real-life cohort of leukemia pts at our institution. Methods: Since 2009, we prospectively analyzed SAD usage on two wards within our department. So far, the total antifungal and concomitant medication of 180 consecutive leukemia pts during antifungal prophylaxis and therapy was analyzed in terms of potential drug interactions using the electronic database Micromedex®. Drug-related adverse events were detected by regular participation on ward rounds, consultation of ward physicians and review of patients' medication charts and laboratory values. In particular, the renal and hepatic function during SAD application was closely assessed. SAD were given according to EORTC-adapted guidelines, with use of fluconazole or posaconazole as primary prophylaxis, and voriconazole, liposomal amphotericin B or caspofungin as therapeutic options. Results: Underlying diseases of the analyzed cohort included AML (n=133), ALL (n=27) and MDS (n=20). Leukemia therapy during analysis predominantly comprised chemotherapy (n=98) and allogeneic hematopoietic stem cell transplantation (n=66). Median SAD costs per analyzed hospital stay in our patient cohort were 2757€ (range: 8–34061€), with 63% of pts inducing costs higher than 1000€. SAD generated 23% of total drug costs in our hematology/oncology department in 2010, thereby ranking second position behind cytostatic agents. Within the analyzed cohort, 83/180 pts received antifungal prophylaxis only, while 97/180 pts received therapeutic regimen involving 1 (n=58), 2 (n=31), 3 (n=6) or 4 (n=2) different SAD in sequence or in combination. Due to drug-related adverse events, SAD application was discontinued or switched to a different drug in 19/180 patients (11%), primarily therapy with voriconazole (7/47, 15%) and liposomal amphotericin B (9/74, 12%). Elevations in creatinine and total bilirubin levels were most frequent during application of liposomal amphotericin B (in 17% and 33% of pts, respectively), while increased levels of alanine transaminase (ALT) were most frequent during use of posaconazole (53% of pts; predominantly CTC grade 1 and 2). Caspofungin was predominantly used in pts with liver predamage, indicated by a median baseline level of total bilirubin of 1.2 mg/dl as compared to ≤ 0.7 mg/dl for all other agents, and showed excellent tolerability. Of note, during the application of SAD, pts received a median number of 25 different concomitant drugs (range 1–54, chemotherapy not included). The proportion of pts exposed to one or more potentially interacting drug combinations involving the respective SAD was: fluconazole 95/102 (93%), caspofungin 16/20 (80%), posaconazole 37/52 (71%), liposomal amphotericin B 52/74 (70%) and voriconazole 33/47 (70%); the number of different potentially interacting drugs for each of these SAD was 17, 4, 9, 6, and 9, respectively. These 45 potentially interacting combinations were rated as moderate (n=27), major (n=17), and contraindicated (n=1) by the drug interaction software. In terms of treatment optimization, therapeutic drug monitoring of posaconazole and voriconazole proved very useful in detecting subtherapeutic levels and showed high inter-pt variability of serum levels. Conclusions: SAD are used intensively in the hematology and oncology setting and require close monitoring of pts' concomitant medication, clinical parameters and laboratory values. This ongoing project at our institution illustrates the use of these drugs in every day clinics, and valuably contributes to a safe and efficient application of this increasingly important class of drugs in our pts. Disclosures: Metzke: MSD Merck Sharp & Dohme GmbH: Research Funding. Engelhardt:MSD Merck Sharp & Dohme GmbH: Research Funding.

P3-011: A FRAILTY INDEX BASED ON ROUTINELY COLLECTED LABORATORY SAFETY DATA PREDICTS ADVERSE EVENTS IN A SEX-SPECIFIC MANNER IN CLINICAL TRIAL SETTINGS

2006 ◽  
Vol 14 (7S_Part_19) ◽  
pp. P1066-P1066
Author(s):  
Taylor Dunn ◽  
Justin Stanley ◽  
Susan E. Howlett ◽  
Arnold B. Mitnitski ◽  
Kenneth Rockwood
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Frailty Index ◽  
Safety Data ◽  
Laboratory Safety ◽  
Specific Manner

Explore the mechanism of Swertia mussotii Franch. for hepatoprotective effects with iTRAQ-LC-MS/MS

2020 ◽  
Vol 23 ◽  
Author(s):  
Haixia Yun ◽  
Xinyu Wu ◽  
Yiwei Ding ◽  
Wendou Xiong ◽  
Xianglan Duan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Aspartate Aminotransferase ◽  
Alanine Aminotransferase ◽  
Total Bilirubin ◽  
Acute Liver Injury ◽  
Proteome Analysis ◽  
Ppi Networks ◽  
Hepatoprotective Effects

Background and Objective : A Tibetan traditional herb named Swertia mussotii Franch., also called “Zangyinchen” by the local people of Qinghai-Tibet area, has been used to protect the liver from injury for many years. However, the curative effect and molecular mechanism of the herb have not been demonstrated clearly. Materials and Methods: In our study, serum alanine aminotransferase, aspartate aminotransferase, total bilirubin levels were examined after S. mussotii Franch. treatment in the acute liver injury of the carbon tetrachloride-induced rat model. Then, Proteome Analysis was applied to explore the potential mechanism of SMT for hepatoprotective effects after iTRAQLC-MS/MS analysis (isobaric tag for relative and absolute quantification-liquid chromatograph-mass spectrometer with tandem mass spectrometry). Results: Serum results showed, alanine aminotransferase, aspartate aminotransferase, total bilirubin levels of rats with acute liver injury were all improved with SMT treatment. Moreover, Proteome Analysis suggested that, with S. Mussotii Franch. treatment, the levels of lipid catabolic process and lipid homeostasis were all enhanced. And the results of protein-protein interaction (PPI) analysis illustrated that these proteins assembled in PPI networks were found almost significantly enriched in response to lipid, negative regulation of lipase activity, response to lipopolysaccharide etc. Furthermore, the downregulated MRP14 and MRP8 proteins were found involved in the lipid metabolism, which may indicate the mechanism of SMT protection liver from ALI induced by carbon tetrachloride. Conclusion: SMT herb could play a role in hepatoprotection and alleviate the effect of acute liver injury by impacting the lipid metabolism associated biological process.

scholarly journals Exploring patient safety outcomes for people with learning disabilities in acute hospital settings: a scoping review

BMJ Open ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. e047102
Author(s):  
Gemma Louch ◽  
Abigail Albutt ◽  
Joanna Harlow-Trigg ◽  
Sally Moore ◽  
Kate Smyth ◽  
...  
Keyword(s):  
Learning Disabilities ◽  
Patient Safety ◽  
Adverse Events ◽  
Grey Literature ◽  
Good Practice ◽  
Hospital Setting ◽  
Eligibility Criteria ◽  
Infant Outcomes ◽  
Safety Outcomes

ObjectivesTo produce a narrative synthesis of published academic and grey literature focusing on patient safety outcomes for people with learning disabilities in an acute hospital setting.DesignScoping review with narrative synthesis.MethodsThe review followed the six stages of the Arksey and O’Malley framework. We searched four research databases from January 2000 to March 2021, in addition to handsearching and backwards searching using terms relating to our eligibility criteria—patient safety and adverse events, learning disability and hospital setting. Following stakeholder input, we searched grey literature databases and specific websites of known organisations until March 2020. Potentially relevant articles and grey literature materials were screened against the eligibility criteria. Findings were extracted and collated in data charting forms.Results45 academic articles and 33 grey literature materials were included, and we organised the findings around six concepts: (1) adverse events, patient safety and quality of care; (2) maternal and infant outcomes; (3) postoperative outcomes; (4) role of family and carers; (5) understanding needs in hospital and (6) supporting initiatives, recommendations and good practice examples. The findings suggest inequalities and inequities for a range of specific patient safety outcomes including adverse events, quality of care, maternal and infant outcomes and postoperative outcomes, in addition to potential protective factors, such as the roles of family and carers and the extent to which health professionals are able to understand the needs of people with learning disabilities.ConclusionPeople with learning disabilities appear to experience poorer patient safety outcomes in hospital. The involvement of family and carers, and understanding and effectively meeting the needs of people with learning disabilities may play a protective role. Promising interventions and examples of good practice exist, however many of these have not been implemented consistently and warrant further robust evaluation.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

scholarly journals Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab

2021 ◽  
Vol 13 ◽  
pp. 175883592110311
Author(s):  
Chiun Hsu ◽  
Lorenza Rimassa ◽  
Hui-Chuan Sun ◽  
Arndt Vogel ◽  
Ahmed O. Kaseb
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Healthcare Providers ◽  
Safety Data ◽  
Standard Of Care ◽  
Antiangiogenic Agents ◽  
Efficacy And Safety ◽  
First Line

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

Cardiovascular, Dermatological, Gastrointestinal, Hematological, Hormonal, and Immunosuppressant Agents

2002 ◽  
Vol 37 (10) ◽  
pp. 1113-1126 ◽  
Author(s):  
Joyce A. Generali
Keyword(s):  
At Risk ◽  
Adverse Events ◽  
Drug Interactions ◽  
Prescription Drugs ◽  
Hospital Pharmacy ◽  
Safety Data ◽  
Black Box ◽  
Information Monitoring ◽  
Black Box Warnings ◽  
Wall Chart

“Black-box” warnings report valuable postmarketing safety data about prescription drugs, keeping practitioners informed about potential adverse events, drug interactions, key dosing information, monitoring and administration requirements, and at-risk patient populations. They are especially crucial for newly approved agents. A list of agents with black-box warnings does not currently exist; however Hospital Pharmacy will be publishing comprehensive lists by drug category in this column until November 2002. At that time, a complete list in wall chart form will be released. Hospital Pharmacy will update the data as salient information becomes available.

Improved quality of reporting safety data of medication in paediatric randomised controlled trials

2021 ◽  
pp. archdischild-2020-321197
Author(s):  
Taco Jan Prins ◽  
Corine Rollema ◽  
Eric van Roon ◽  
Tjalling de Vries
Keyword(s):  
Adverse Events ◽  
Randomised Controlled Trials ◽  
Safety Data ◽  
Drug Event ◽  
Controlled Trials ◽  
Quality Of Reporting ◽  
Event Reporting ◽  
The Past ◽  
Randomised Controlled

ObjectiveEvaluating the reporting of safety data of medication in paediatric randomised controlled trials (RCTs) in 2017–2018 compared with our earlier study.DesignLiterature search with a systemic appraisal of adverse drug event reporting.Main outcome measuresQuality of reporting of safety data using Consolidated Standards of Reporting Trials (CONSORT) and Ioannidis scores in paediatric drug RCTs. The CONSORT score consists of nine recommendations of the CONSORT Group issued to improve the quality of reporting adverse events. The Ioannidis score is based on these advices. We considered a CONSORT score of at least 6 and an Ioannidis score of at least 3 as sufficient.ResultsWe reviewed 100 RCTs published in 2017 and 2018. Ninety-four (94%) articles mentioned adverse events compared with 78% in the earlier study. Fifty-seven per cent used a standardised method for reporting adverse events compared with 34% in our earlier study. In 26 of the articles, the expected adverse events were defined, and 27 articles had a preset standardised scale for adverse events. Of these, 62 articles (62%) had a CONSORT score of 6 or higher compared with 18% in 2010. In the present study, 67% had an Ioannidis score of 3 or higher, whereas in the earlier study this was 29%. Both differences are statistically significant (p<0.05).ConclusionsReporting safety data in paediatric RCTs has improved over the past 10 years. However, there is still room for improvement and for further improvement. Authors and editors should give more attention to methods for collecting, reporting and presenting safety data of RCTs in studies and manuscripts.

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