Hemophilia trials in the twenty‐first century: Defining patient important outcomes

Konkle, Barbara A.; Skinner, Mark W.; Iorio, Alfonso

doi:10.1002/rth2.12195

Cited by 44 publications

(69 citation statements)

References 93 publications

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“…Some articles did not differentiate between patient-reported and patient-relevant outcomes [37][38][39]. Other articles emphasized a potential overlap of the terms, but noted that not every outcome which can be reported by patients necessarily has to be relevant for them [16,18,23,24,41]. Two articles on chronically ill children expanded the terminology from patients to the family to underline the social context and impact [21,36].…”

Section: Discussionmentioning

confidence: 99%

“…Transferring this to practice implies that patient-driven approaches are required: Patients or representatives need to be asked when defining what is relevant for them. Referring to the patients' orin the case of young children or critical carethe caregivers' opinions, such patientdriven approaches were identified in 14 articles included in our scoping review, but were limited to specific diseases such as cardiovascular disorders [11][12][13][15][16][17][18][19][20][21][22][23][24][25]. For these particular patients, adverse events like myocardial infarction or stroke might be important outcomes but may not necessarily be applicable to other patient groups as specific diseases are commonly associated with very specific needs and preferences that cannot be generalized.…”

Section: Discussionmentioning

confidence: 99%

“…In about one third (n = 13, 29.5%) of the 44 articles analyzed, no reason was provided why the outcomes reported were considered to be relevant to patients (Table 4). However, in other studies we found different explanations justifying the selection of patient-relevant outcomes that refer mainly to three core issues: [14,26] or to both patients' and experts' opinion (n = 5) [11,12,18,19,21]. One study on early childhood disease included caregivers instead of patients [21], another one on critical disease included caregivers in addition to patients [13].…”

Section: Justificationmentioning

confidence: 91%

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Patient-relevant outcomes: what are we talking about? A scoping review to improve conceptual clarity

Kersting

Kneer

Barzel

2020

BMC Health Serv Res

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Background: With respect to patient-centered care, measuring care effects based on patient-relevant outcomes is becoming increasingly important. There is some uncertainty about what outcomes are particularly relevant to patients and who determines their relevance. To determine this, we conducted a scoping review of the international literature with the aim to improve the conceptual clarity regarding (1) the terminology used for supposedly patient-relevant outcomes, (2) the variety of outcomes considered patient-relevant, and (3) justifications for the choice of these specific outcomes. Methods: We conducted a systematic search in Embase, PubMed (including Medline), Cochrane Central, Scopus, and Google Scholar with a special focus on article titles. Search terms included patient-relevant, patient-important, patient-preferred, and outcome(s), endpoint(s), parameter(s), indicator(s). We limited the search period from January 2000 to July 2019. Full-text articles reporting outcomes that were described as patient-relevant met the inclusion criteria. Two researchers independently analyzed all eligible articles applying quantitative and structuring content analysis. Results: We identified 155 articles, 44 of which met the inclusion criteria. A content analysis revealed 35 different terms used with regard to patient-relevant outcomes. However, authors predominantly referred to patientimportant outcomes (23 articles, 52.3%) and patient-relevant outcomes (17 articles, 38.6%). A structuring content analysis of all extracted outcomes revealed a total of 281 codes, pooled in 32 inductive categories. Among these, the following categories dominated: symptoms, adverse events/complications, survival/mortality, pain. In just 16 of the articles (36.4%), authors provided justifications for the choice of the outcome being based either on patient and/or expert opinions. In another 13 articles (29.5%), no justification was provided. Conclusion: This scoping review on patient-relevant outcomes was driven by the questions (1) what outcomes are particularly relevant to patients, and (2) who determines their relevance. We found a wide range of supposedly patientrelevant outcomes, with only one third of articles involving patients in the justification of the outcome selection. In view of this conceptual uncertainty it appears difficult to determine or even to compare a particular patient benefit of interventions. A set of generic outcomes relevant to patients would be helpful to contribute to a consistent understanding of patient relevance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Justificationmentioning

confidence: 91%

See 1 more Smart Citation

Patient-relevant outcomes: what are we talking about? A scoping review to improve conceptual clarity

Kersting

Kneer

Barzel

2020

BMC Health Serv Res

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“…3,8,14 These will carry common and unique risks and benefits compared with AAV-mediated gene therapy and postmarketing surveillance will need to be adaptable to new safety signals and new endpoints as the field evolves. 15 Additionally, registration trials are being performed in a healthy subset of patients, and restrict use of comedications, thereby reducing the likelihood of detecting disease-drug and drug-drug interactions. 16 A collaborative global strategy is required to ensure a large enough patient pool to allow robust evaluation and detection of low incident events that may otherwise go undetected.…”

Section: Discussionmentioning

confidence: 99%

Core data set on safety, efficacy, and durability of hemophilia gene therapy for a global registry: Communication from the SSC of the ISTH

Konkle

Pierce

Coffin

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Gene therapy for people with hemophilia (PWH) will soon become available outside current clinical trials. The World Federation of Hemophilia (WFH), in collaboration with International Society of Thrombosis and Hemostasis Scientific and Standardization Committee (ISTH SSC), the European Haemophilia Consortium (EHC), the US National Hemophilia Foundation (NHF), the American Thrombosis and Hemostasis Network (ATHN), industry gene therapy development partners and Regulatory liaisons have developed the Gene Therapy Registry (GTR), designed to collect long-term data on all PWH who receive hemophilia gene therapy. Objective: The objectives of the GTR are to record the long-term safety and efficacy data post gene therapy infusion and to assess the changes in quality of life and burden of disease post-gene-therapy infusion. Methods: The GTR is a prospective, observational, and longitudinal registry developed under the guidance of a multi-stakeholder GTR Steering Committee (GTR SC), composed of health care professionals, patient advocates, industry representatives, and regulatory agency liaisons. All PWH who receive gene therapy by clinical trial or commercial product will be invited to enrol in the registry through their hemophilia treatment centers (HTCs). The registry aims to recruit 100% of eligible post gene therapy PWH globally. Through an iterative process, and following the guidance of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), the GTR SC has developed a core set of data to be collected on all patients post gene therapy. Results: The core data set includes demographic information, vector infusion details, safety, efficacy, quality of life and burden of disease. | 3075 KONKLE Et aL.

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“…patterns; and, currently, mechanisms for greater or lesser bleeding remain unclear. [81][82][83][84][85][86][87][88][89][90] The pro-hemostatic property of SkM in hemophilic mice leads to the speculation that differences in levels of plasma procoagulant SkM might influence hemostasis and bleeding in severe hemophilia A patients where procoagulant plasma myosin isoforms could reduce the risk of bleeding in severe hemophilia A patients. This speculation merits assessment in studies that evaluate the various SkM phenotypes among severe hemophilia A patients.…”

Section: Procoagulant Activity Of Skm and CM In Murine Tail Bleedinmentioning

confidence: 99%

Novel blood coagulation molecules: Skeletal muscle myosin and cardiac myosin

Deguchi

Morla

Griffin

2021

Journal of Thrombosis and Haemostasis

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Striated muscle myosins can promote prothrombin activation by FXa or FVa inactivation by APC. Cardiac myosin and skeletal muscle myosin are pro‐hemostatic in murine tail cut bleeding models. Infused cardiac myosin exacerbates myocardial injury caused by myocardial ischemia reperfusion. Skeletal muscle myosin isoforms that circulate in human plasma can be grouped into 3 phenotypes. Abstract Two striated muscle myosins, namely skeletal muscle myosin (SkM) and cardiac myosin (CM), may potentially contribute to physiologic mechanisms for regulation of thrombosis and hemostasis. Thrombin is generated from activation of prothrombin by the prothrombinase (IIase) complex comprising factor Xa, factor Va, and Ca++ ions located on surfaces where these factors are assembled. We discovered that SkM and CM, which are abundant motor proteins in skeletal and cardiac muscles, can provide a surface for thrombin generation by the prothrombinase complex without any apparent requirement for phosphatidylserine or lipids. These myosins can also provide a surface that supports the inactivation of factor Va by activated protein C/protein S, resulting in negative feedback downregulation of thrombin generation. Although the physiologic significance of these reactions remains to be established for humans, substantive insights may be gleaned from murine studies. In mice, exogenously infused SkM and CM can promote hemostasis as they are capable of reducing tail cut bleeding. In a murine myocardial ischemia‐reperfusion injury model, exogenously infused CM exacerbates myocardial infarction damage. Studies of human plasmas show that SkM antigen isoforms of different MWs circulate in human plasma, and they can be used to identify three plasma SkM phenotypes. A pilot clinical study showed that one SkM isoform pattern appeared to be linked to isolated pulmonary embolism. These discoveries enable multiple preclinical and clinical studies of SkM and CM, which should provide novel mechanistic insights with potential translational relevance for the roles of CM and SkM in the pathobiology of hemostasis and thrombosis.

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Hemophilia trials in the twenty‐first century: Defining patient important outcomes

Cited by 44 publications

References 93 publications

Patient-relevant outcomes: what are we talking about? A scoping review to improve conceptual clarity

Patient-relevant outcomes: what are we talking about? A scoping review to improve conceptual clarity

Core data set on safety, efficacy, and durability of hemophilia gene therapy for a global registry: Communication from the SSC of the ISTH

Novel blood coagulation molecules: Skeletal muscle myosin and cardiac myosin

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