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1.
Trials ; 22(1): 376, 2021 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-34078421

RESUMEN

BACKGROUND: Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime. METHODS: This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan® 4% and Sterofundin® ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin® ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28 days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits/calls will be scheduled on day 28 and day 90. DISCUSSION: This study aims to generate evidence regarding which regimen-a gelatine-crystalloid regimen or a pure crystalloid regimen-is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload. TRIAL REGISTRATION: The European clinical trial database EudraCT 2015-000057-20 and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov NCT02715466 . Registered on 17 March 2016.


Asunto(s)
Sepsis , Choque Séptico , Ensayos Clínicos Fase IV como Asunto , Electrólitos , Fluidoterapia , Gelatina/efectos adversos , Humanos , Unidades de Cuidados Intensivos , Volumen Plasmático , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Sepsis/diagnóstico , Sepsis/terapia , Choque Séptico/diagnóstico , Choque Séptico/terapia
2.
Cancer Immunol Immunother ; 70(6): 1735-1743, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33388995

RESUMEN

Aging is considered the single most significant risk factor for the majority of common malignances including lung cancer. Together immunosenescence, changes occurring with aging in the immune system, and inflammaging, characterizes by a chronic, subclinical accumulation of pro-inflammatory factors, are suggested to stand at the origin of most of the diseases of the elderly, such as cancer. The aim of this study was to determine associations among lymphocyte subpopulations, pro-inflammatory cytokines and epidermal growth factor (EGF) in patients diagnosed with non-small cell lung cancer (NSCLC). Forty-six advanced NSCLC patients were enrolled. Sixteen patients with newly diagnosed and before treatment and 30 patients after first-line platinum-based chemotherapy. Peripheral blood subpopulations were studied by flow cytometry and serum concentrations of soluble factors by ELISA. The frequency of naïve CD4+ T cells, naïve B cells and central memory CD8+ T cells were significantly lower in NSCLC patients after chemotherapy, while effector memory CD4+ T cells and terminally differentiated CD8+ T cells were significantly higher. IL-1ß and TNFα significantly correlated among them before and after platinum-based chemotherapy. Terminally differentiated T cells expressing CD57+ significantly correlated with TNFα and IL-1ß. For the first time, associations between EGF serum levels and terminally differentiated CD4+ T cells, and memory B cells were detected. This study confirms the association among terminally differentiated lymphocytes and pro-inflammatory cytokines in patients diagnosed with lung cancer, reinforcing the interconnection between terminally differentiated lymphocytes and pro-inflammatory cytokines. Clinical trial registration number: RPCEC00000205, http://registroclinico.sld.cu/.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/patología , Citocinas/metabolismo , Factor de Crecimiento Epidérmico/metabolismo , Neoplasias Pulmonares/patología , Subgrupos Linfocitarios/inmunología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ensayos Clínicos Fase IV como Asunto , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Pronóstico
3.
Trials ; 22(1): 100, 2021 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-33509275

RESUMEN

BACKGROUND: The Randomized Embedded Multifactorial Adaptive Platform for COVID-19 (REMAP-COVID) trial is a global adaptive platform trial of hospitalized patients with COVID-19. We describe implementation at the first US site, the UPMC health system, and offer recommendations for implementation at other sites. METHODS: To implement REMAP-COVID, we focused on six major areas: engaging leadership, trial embedment, remote consent and enrollment, regulatory compliance, modification of traditional trial management procedures, and alignment with other COVID-19 studies. RESULTS: We recommend aligning institutional and trial goals and sharing a vision of REMAP-COVID implementation as groundwork for learning health system development. Embedment of trial procedures into routine care processes, existing institutional structures, and the electronic health record promotes efficiency and integration of clinical care and clinical research. Remote consent and enrollment can be facilitated by engaging bedside providers and leveraging institutional videoconferencing tools. Coordination with the central institutional review board will expedite the approval process. Protocol adherence, adverse event monitoring, and data collection and export can be facilitated by building electronic health record processes, though implementation can start using traditional clinical trial tools. Lastly, establishment of a centralized institutional process optimizes coordination of COVID-19 studies. CONCLUSIONS: Implementation of the REMAP-COVID trial within a large US healthcare system is feasible and facilitated by multidisciplinary collaboration. This investment establishes important groundwork for future learning health system endeavors. TRIAL REGISTRATION: NCT02735707 . Registered on 13 April 2016.


Asunto(s)
COVID-19/terapia , Infecciones Comunitarias Adquiridas/terapia , Neumonía/terapia , Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Ensayos Clínicos Fase IV como Asunto , Medicina Basada en la Evidencia , Humanos , Estudios Multicéntricos como Asunto , Sistemas de Atención de Punto , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2
4.
Trials ; 22(1): 95, 2021 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-33499921

RESUMEN

BACKGROUND: Epidemiological studies have shown that young women often suffer from primary dysmenorrhea (PD) which is a common cause that affects their routine work and quality of life. Chinese herbal medicine has been widely used for PD in China. A systematic review found that Xuefu Zhuyu (XFZY) has a promising effect on PD management, yet there is a dearth of high-quality evidence in support of this claim. We want to conduct a randomized controlled trial to evaluate the efficacy and safety of XFZY for PD patients. METHODS: This is a protocol for a multicenter, randomized, placebo-controlled trial. A total of 248 participants with PD will be recruited at 6 centers and randomized into two groups-a herbal treatment group and a placebo group. The participants will receive either XFZY or placebo, three times per day, for 3 menstrual cycles, with a 12-week follow-up. The primary outcome will be the mean change in pain intensity as measured by VAS, while the change in menstrual pain duration, the change in peak pain intensity as measured by VAS, the Cox Menstrual Symptom Scale (CMSS), quality of life EQ-5D-5L, cumulative painkiller consumption, and health economics will be included as secondary outcomes. Adverse events will also be reported. DISCUSSION: This protocol describes a multicenter, double-blind, randomized, placebo-controlled trial that investigates the efficacy and safety of XFZY for primary dysmenorrhea. Validated evaluation tools will assess dysmenorrhea severity. We believe that this research will provide important evidence regarding the use of XFZY to treat dysmenorrhea. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900026819 . Registered on 23 October 2019.


Asunto(s)
Medicamentos Herbarios Chinos/administración & dosificación , Dismenorrea/tratamiento farmacológico , Adolescente , Adulto , Analgésicos/administración & dosificación , China , Ensayos Clínicos Fase IV como Asunto , Método Doble Ciego , Esquema de Medicación , Medicamentos Herbarios Chinos/efectos adversos , Dismenorrea/complicaciones , Dismenorrea/diagnóstico , Dismenorrea/psicología , Femenino , Humanos , Estudios Multicéntricos como Asunto , Dimensión del Dolor/estadística & datos numéricos , Placebos/administración & dosificación , Placebos/efectos adversos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
5.
Am Heart J ; 234: 133-135, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33347871

RESUMEN

Clinical trials provide the foundational evidence that guide many patient-facing decisions; however, the therapeutic effect and safety of an intervention is best evaluated when compared to a control group. We used ClinicalTrials.gov to describe the proportion of registered Phase III and IV cardiovascular clinical trials that contain a control group from 2009 through 2019. Of 1,677 registered Phase III and IV cardiovascular clinical trials, 81.2% contain a control group, and the annual prevalence remained unchanged between 2009 and 2019.


Asunto(s)
Enfermedades Cardiovasculares/terapia , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase IV como Asunto/estadística & datos numéricos , Grupos Control , Bases de Datos Factuales/estadística & datos numéricos , National Library of Medicine (U.S.)/estadística & datos numéricos , Humanos , Estados Unidos
6.
Am Heart J ; 226: 49-59, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32502882

RESUMEN

Angiotensin-converting enzyme-2 (ACE2) expression may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs). Because renin-angiotensin system blockers increase levels of ACE2, a protein that facilitates coronavirus entry into cells, there is concern that these drugs could increase the risk of developing a severe and fatal form of COVID-19. The impact of discontinuing ACEI and ARBs in patients with COVID-19 remains uncertain. DESIGN: BRACE CORONA is a pragmatic, multicenter, randomized, phase IV, clinical trial that aims to enroll around 500 participants at 34 sites in Brazil. Participants will be identified from an ongoing national registry of suspected and confirmed cases of COVID-19. Eligible patients using renin-angiotensin system blockers (ACEI/ARBs) with a confirmed diagnosis of COVID-19 will be randomized to a strategy of continued ACEI/ARB treatment versus temporary discontinuation for 30 days. The primary outcome is the median days alive and out of the hospital at 30 days. Secondary outcomes include progression of COVID-19 disease, all-cause mortality, death from cardiovascular causes, myocardial infarction, stroke, transient ischemic attack, new or worsening heart failure, myocarditis, pericarditis, arrhythmias, thromboembolic events, hypertensive crisis, respiratory failure, hemodynamic decompensation, sepsis, renal failure, and troponin, B-type natriuretic peptide (BNP), N-terminal-proBNP, and D-dimer levels. SUMMARY: BRACE CORONA will evaluate whether the strategy of continued ACEI/ARB therapy compared with temporary discontinuation of these drugs impacts clinical outcomes among patients with COVID-19.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Ensayos Clínicos Pragmáticos como Asunto , Brasil , Ensayos Clínicos Fase IV como Asunto , Humanos , Pacientes Internos , Estudios Multicéntricos como Asunto , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Sistema Renina-Angiotensina/fisiología , Integración Viral , Privación de Tratamiento
7.
Trials ; 21(1): 491, 2020 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-32503663

RESUMEN

OBJECTIVES: The hypothesis of the proposed intervention is that Granulocyte-macrophage colony-stimulating factor (GM-CSF) has profound effects on antiviral immunity, and can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. Sargramostim is a man-made form of the naturally-occurring protein GM-CSF. TRIAL DESIGN: A phase 4 academic, prospective, 2 arm (1:1 ratio), randomized, open-label, controlled trial. PARTICIPANTS: Patients aged 18-80 years admitted to specialized COVID-19 wards in 5 Belgian hospitals with recent (< 2 weeks prior to randomization) confirmed COVID-19 infection and acute respiratory failure defined as a PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen. Patients were excluded from the trial in case of (1) known serious allergic reactions to yeast-derived products, (2) lithium carbonate therapy, (3) mechanical ventilation prior to randomization, (4) peripheral white blood cell count above 25.000/µL and/or active myeloid malignancy, (5) high dose systemic steroid therapy (> 20 mg methylprednisolone or equivalent), (6) enrolment in another investigational study, (7) pregnant or breastfeeding or (8) ferritin levels > 2000 µg/mL. INTERVENTION AND COMPARATOR: Inhaled sargramostim 125 µg twice daily for 5 days in addition to standard care. Upon progression of disease requiring mechanical ventilation or to acute respiratory distress syndrome (ARDS) and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125 µg/m2 body surface area once daily until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment. Intervention will be compared to standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards in the standard of care group will have the option (clinician's decision) to initiate IV sargramostim 125m µg/m2 body surface area once daily for 5 days. MAIN OUTCOMES: The primary endpoint of this intervention is measuring oxygenation after 5 days of inhaled (and intravenous) treatment through assessment of a change in pretreatment and post-treatment ratio of PaO2/FiO2 and through measurement of the P(A-a)O2 gradient (PAO2= Partial alveolar pressure of oxygen, PaO2=Partial arterial pressure of oxygen; FiO2= Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 1:1 ratio. Randomization will be done using REDCap (electronic IWRS system). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 80 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be enrolled, 40 in the active and 40 in the control group. TRIAL STATUS: SARPAC protocol Version 2.0 (April 15 2020). Participant recruitment is ongoing in 5 Belgian Hospitals (i.e. University Hospital Ghent, AZ Sint-Jan Bruges, AZ Delta Roeselare, University Hospital Brussels and ZNA Middelheim Antwerp). Participant recruitment started on March 26th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on March 30th, 2020 (ClinicalTrials.gov Identifier: NCT04326920) - retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT04326920?term=sarpac&recrs=ab&draw=2&rank=1 and on EudraCT on March 24th, 2020 (Identifier: 2020-001254-22). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neumonía Viral/complicaciones , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Respiratoria/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase IV como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Pandemias , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Respiración Artificial , Adulto Joven
9.
Trials ; 21(1): 13, 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31907007

RESUMEN

BACKGROUND: Infliximab (INX) and other tumour necrosis factor inhibitors (TNFi) have revolutionised the treatment of several immune mediated inflammatory diseases. Still, many patients do not respond sufficiently to therapy or lose efficacy over time. The large interindividual variation in serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be major reasons for treatment failures. Therapeutic drug monitoring (TDM), an individualised treatment strategy based on systematic assessments of serum drug concentrations, has been proposed as a clinical tool to optimise efficacy of INX treatment. TDM seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy has not yet been demonstrated in randomised clinical trials. The NORwegian DRUg Monitoring study (NOR-DRUM) aims to assess the effectiveness of TDM, both with regard to the achievement of remission in patients starting INX treatment (part A) as well as to maintain disease control in patients on INX treatment (part B). METHODS: The NOR-DRUM study is a randomised, open, controlled, parallel-group, comparative, multi-centre, national, superiority, phase IV study with two separate parts, NOR-DRUM A and NOR-DRUM B. Patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn's disease and psoriasis are included. In both study parts participants are randomised 1:1 to either TDM of infliximab (intervention group) or to standard treatment with infliximab without knowledge of drug levels or ADAb status (control group). NOR-DRUM A will include 400 patients starting INX therapy. The primary outcome is remission at 30 weeks. In NOR-DRUM B, 450 patients on maintenance treatment with INX will be included. The primary endpoint is occurrence of disease worsening during the 52-week study period. DISCUSSION: As the first trial to assess the effectiveness, safety and cost-effectiveness of TDM in patients receiving TNFi for a range of immune mediated inflammatory diseases, we hope that the NOR-DRUM study will contribute to the advancement of evidence based personalised treatment with biological medicines. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03074656. Registered on 090317.


Asunto(s)
Antirreumáticos/uso terapéutico , Monitoreo de Drogas , Infliximab/uso terapéutico , Adulto , Anciano , Antirreumáticos/farmacocinética , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Ensayos Clínicos Fase IV como Asunto , Colitis Ulcerosa/sangre , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/sangre , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Humanos , Infliximab/farmacocinética , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Noruega , Psoriasis/sangre , Psoriasis/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Espondilitis Anquilosante/sangre , Espondilitis Anquilosante/tratamiento farmacológico , Resultado del Tratamiento , Adulto Joven
10.
Trials ; 21(1): 24, 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31907033

RESUMEN

BACKGROUND: Although the wound-healing period for purse-string closure (PSC) after stoma reversal is longer than that required for the primary closure method, the rate of wound infection is reduced. The application of negative-pressure wound therapy (NPWT) can reduce the healing period for many types of wounds. Herein, we describe a planned trial to test the hypothesis that NPWT can reduce the healing period for PSC after stoma reversal. METHODS/DESIGN: Patients undergoing stoma reversal will be recruited and allocated into intervention and control groups, with 1:1 randomisation. Patients in the control group will receive standard postsurgical wound care; patients in the intervention group will receive NPWT using the PICO™ system. The target sample size will be 38 patients, as this will provide 80% power at the 5% level of significance to detect a 7-day reduction in the wound-healing period in the intervention group compared to that in the control group. The primary endpoint will be the duration to wound healing, defined as the time to nearly complete epithelisation of the wound, without any discharge or surgical site infection (SSI). Secondary endpoints will be the SSI rate, length of postoperative hospital stay, number of wound dressings and visits to the hospital for wound dressing after discharge, total cost of wound dressings, and patient and observer scar assessment scale scores. DISCUSSION: The results of this planned randomised controlled study will clarify the role of NPWT in patients undergoing stoma reversal and strengthen the rationale for choosing a dressing technique. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0004063. Registered on 6 June 2019.


Asunto(s)
Terapia de Presión Negativa para Heridas , Repitelización , Estomas Quirúrgicos/efectos adversos , Infección de la Herida Quirúrgica/prevención & control , Técnicas de Cierre de Heridas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Vendajes/economía , Vendajes/estadística & datos numéricos , Ensayos Clínicos Fase IV como Asunto , Femenino , Humanos , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Terapia de Presión Negativa para Heridas/economía , Terapia de Presión Negativa para Heridas/instrumentación , Terapia de Presión Negativa para Heridas/estadística & datos numéricos , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Piel/fisiopatología , Infección de la Herida Quirúrgica/etiología , Infección de la Herida Quirúrgica/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
11.
Viruses ; 13(1)2020 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-33396343

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted primarily through respiratory droplets/aerosols and it causes COVID-19. The virus infects epithelial cells by using the spike protein on its surface to bind to angiotensin-converting enzyme 2 receptor on the cells. Thus, candidate vaccines targeting the spike protein are currently being developed to prevent against infections. Approximately 44 SARS-CoV-2 candidate vaccines are in clinical trials (phase I-III) and an additional 164 candidates are in preclinical stages. The efficacy data from phase I/II trials of lead candidate vaccines look very promising with virus-neutralizing geometric mean antibody titers in the range of 16.6-3906. Most recently, two SARS-CoV-2 candidate vaccines, BNT162b2 and mRNA-1273, have been granted the first emergency use authorization (EUA) in the U.S.; BNT162b2 has also been granted an EUA in the United Kingdom, Canada, and in the European Union. This review assesses whether SARS-CoV-2 candidate vaccines (with approved EUA or in phase III trials) meet the criteria for an ideal SARS-CoV-2 vaccine. The review concludes with expectations from phase III trials and recommendations for phase IV studies (post-vaccine approval).


Asunto(s)
Vacunas contra la COVID-19 , COVID-19/prevención & control , Aprobación de Drogas , SARS-CoV-2 , Anticuerpos Neutralizantes/inmunología , Canadá , Ensayos Clínicos como Asunto , Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Fase IV como Asunto , Europa (Continente) , Humanos , Glicoproteína de la Espiga del Coronavirus/inmunología , Reino Unido , Estados Unidos , Vacunas Sintéticas
12.
Bioanalysis ; 11(22): 2049-2060, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31829738

RESUMEN

Aim: To develop and validate a simple method using UPLC-MS/MS for determination of apatinib and its three active metabolites in a Phase IV clinical trial. Materials & methods: All compounds were separated on a Hypersil GOLD™ aQ C18 Polar Endcapped LC column (50 × 2.1 mm, 1.9 µm, Thermo) using 5 mmol/l ammonium acetate with 0.1% formic acid:acetonitrile (20:80, v/v) as the mobile phase after a rapid liquid-liquid extraction. This method was validated over the linear concentration range of 1.00-1000 ng/ml for each compound. Results: The interassay precision and accuracy were less than ±15%. The validated method was successfully applied to determine concentrations of clinical samples in non-small-cell lung cancer patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Ensayos Clínicos Fase IV como Asunto , Neoplasias Pulmonares/metabolismo , Piridinas/metabolismo , Espectrometría de Masas en Tándem/métodos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Límite de Detección , Modelos Lineales , Extracción Líquido-Líquido , Neoplasias Pulmonares/tratamiento farmacológico , Piridinas/aislamiento & purificación , Piridinas/uso terapéutico
13.
Trials ; 20(1): 754, 2019 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-31856900

RESUMEN

BACKGROUND: Current international guidelines recommend the use of a daily topical exit-site antimicrobial to prevent peritoneal dialysis (PD)-related infections. Although nonantibiotic-based therapies are appealing because they may limit antimicrobial resistance, no controlled trials have been conducted to compare topical antimicrobial agents with usual exit-site care for the prevention of PD-related infections among the Thai PD population. We propose a controlled three-arm trial to examine the efficacy and safety of a daily chlorhexidine gluconate-impregnated patch versus mupirocin ointment versus usual exit-site care with normal saline for the prevention of PD-related infections. METHODS/DESIGNS: This study is a randomized, double-blind, multicenter, active-controlled, clinical trial. Adult patients aged 18 years or older who have end-stage kidney disease and are undergoing PD will be enrolled at three PD Centers in Thailand. A total of 354 PD patients will be randomly assigned to either the 2% chlorhexidine gluconate-impregnated patch, mupirocin ointment, or usual exit-site care with normal saline dressing according to a computer-generated random allocation sequence. Participants will be followed until discontinuation of PD or completion of 24 months. The primary study outcomes are time to first PD-related infection (exit-site/tunnel infection or peritonitis) event and the overall difference in PD-related infection rates between study arms. Secondary study outcomes will include (i) the rate of infection-related catheter removal and PD technique failure, (ii) rate of nasal and exit-site Staphylococcus aureus colonization, (iii) healthcare costs, and (iv) skin reactions and adverse events. We plan to conduct a cost-utility analysis alongside the trial from the perspectives of patients and society. A Markov simulation model will be used to estimate the total cost and health outcome in terms of quality-adjusted life years (QALYs) over a 20-year time horizon. An incremental cost-effectiveness ratio in Thai Baht and U.S. dollars per QALYs gained will be illustrated. A series of probabilistic sensitivity analyses will be conducted to assess the robustness of the cost-utility analysis findings. DISCUSSION: The results from this study will provide new clinical and cost-effectiveness evidence to support the best strategy for the prevention of PD-related infections among the Thai PD population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02547103. Registered on September 11, 2015.


Asunto(s)
Antibacterianos/administración & dosificación , Antiinfecciosos Locales/administración & dosificación , Infecciones Relacionadas con Catéteres/epidemiología , Diálisis Peritoneal/efectos adversos , Peritonitis/epidemiología , Infecciones Estafilocócicas/epidemiología , Administración Tópica , Adulto , Anciano , Antibacterianos/economía , Antiinfecciosos Locales/economía , Infecciones Relacionadas con Catéteres/diagnóstico , Infecciones Relacionadas con Catéteres/microbiología , Infecciones Relacionadas con Catéteres/prevención & control , Catéteres de Permanencia/efectos adversos , Clorhexidina/administración & dosificación , Clorhexidina/análogos & derivados , Ensayos Clínicos Fase IV como Asunto , Análisis Costo-Beneficio , Método Doble Ciego , Costos de los Medicamentos , Femenino , Humanos , Incidencia , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Mupirocina/administración & dosificación , Mucosa Nasal/microbiología , Diálisis Peritoneal/instrumentación , Peritonitis/diagnóstico , Peritonitis/microbiología , Peritonitis/prevención & control , Proyectos Piloto , Ensayos Clínicos Controlados Aleatorios como Asunto , Solución Salina/administración & dosificación , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/prevención & control , Staphylococcus aureus/aislamiento & purificación , Resultado del Tratamiento
14.
Trials ; 20(1): 748, 2019 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-31856903

RESUMEN

BACKGROUND: While the efficacy of cognitive therapy (CT) has been well established for social anxiety disorder (SAD) in several randomized controlled trials, there are still large differences between trials with respect to effect sizes. The present study investigates the question of whether enhanced training and the use of behavioral experiments (BEs) increases the efficacy of traditional CT, based on verbal methods of cognitive restructuring. METHODS/DESIGN: A mixed within/between conditions design will be applied, with therapists and patients being randomly allocated to one of two conditions: (1) training of CT plus BEs, (2) training of CT "as usual". Sixty patients with the primary diagnosis of SAD will be recruited and treated in the outpatient clinic of the Department of Psychology, University of Frankfurt. To ensure adherence to therapist protocols, all therapists will be trained and supervised by the project coordinators. In addition, videotaped treatment sessions will be independently evaluated to guarantee both adherence to protocols and the quality of the intervention. Treatment effects will be assessed by independent SAD symptom ratings using the Liebowitz Social Anxiety Scale as the primary outcome measure and self-report measures as secondary outcome measures. DISCUSSION: The present cognitive behavioral therapy (CBT) trial will be the first to clarify the contribution of BEs to the efficacy of CT in a randomized controlled design. Study results are relevant to clinical training and implementation of evidence-based treatments. TRIAL REGISTRATION: German Clinical Trials Register International Clinical Trials Registry Platform (ICTRP) identifier: DRKS00014349. Trial status: recruiting.


Asunto(s)
Terapia Cognitivo-Conductual/métodos , Fobia Social/terapia , Adolescente , Adulto , Anciano , Ensayos Clínicos Fase IV como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fobia Social/diagnóstico , Fobia Social/psicología , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Autoinforme , Resultado del Tratamiento , Adulto Joven
15.
BMJ Open ; 9(12): e033774, 2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-31852711

RESUMEN

INTRODUCTION: Dual antiplatelet therapy (DAPT) with aspirin and thienopyridine is required after placement of coronary stents to prevent thrombotic complications. However, current recommendation for duration of DAPT remains controversial. Firehawk is a biodegradable polymer applied to recessed abluminal grooves, sirolimus target-eluting stent associated with early excellent healing response and almost complete strut coverage, as well as possibly reduced myocardial ischaemic events. But the optimal DAPT duration for such a new generation stent is less known. Therefore, the present trial seeks to evaluate the safety and efficacy of 3-month versus 12-month DAPT in broad patients receiving Firehawk stents. METHODS AND ANALYSIS: The TARGET DAPT study is designed to access the benefits and risks of short-term (3 months) versus long-term (12 months) DAPT in preventing stent thrombosis or major adverse cardiovascular and cerebrovascular events in subjects undergoing percutaneous coronary intervention for the treatment of coronary artery obstructive lesions. The TARGET DAPT trial is a large, prospective, multicentre, randomised (1:1) non-inferiority clinical trial that will enrol 2446 subjects treated with Firehawk stents. The primary endpoint is net adverse clinical and cerebral events, a composite of all-cause death, myocardial infarction, cerebral vascular accident and major bleeding (BARC 2,3 or 5) at 18 months clinical follow-up postindex procedure. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of Zhongshan Hospital, Shanghai. The reference number is B2018-146R. Study findings will be made available to interested participants. Study results will be submitted for publication in a peer-reviewed journal. Also the protocol will be submitted and approved by the institutional Ethics Committee at each participating clinical centre. TRIAL REGISTRATION: NCT03008083.


Asunto(s)
Aspirina/administración & dosificación , Estenosis Coronaria/terapia , Stents Liberadores de Fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Sirolimus/administración & dosificación , Implantes Absorbibles , China , Ensayos Clínicos Fase IV como Asunto , Angiografía Coronaria , Estenosis Coronaria/diagnóstico por imagen , Esquema de Medicación , Terapia Antiplaquetaria Doble/efectos adversos , Estudios de Equivalencia como Asunto , Hemorragia/etiología , Humanos , Estudios Multicéntricos como Asunto , Infarto del Miocardio/etiología , Intervención Coronaria Percutánea , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Trombosis/etiología
16.
BMJ Open ; 9(11): e032549, 2019 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-31727664

RESUMEN

INTRODUCTION: Rotavirus vaccines were introduced into the Australian National Immunisation Program in 2007. Despite this, Northern Territory Indigenous children continue to be hospitalised with rotavirus at a rate more than 20 times higher than non-Indigenous children in other Australian jurisdictions, with evidence of waning protection in the second year of life. We hypothesised that scheduling an additional (third) dose of oral human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to <12 months would improve protection against clinically significant all-cause gastroenteritis. METHODS AND ANALYSIS: This Bayesian adaptive clinical trial will investigate whether routinely scheduling an additional dose of Rotarix for Australian Indigenous children aged 6 to <12 months old confers significantly better protection against clinically important all-cause gastroenteritis than the current two-dose schedule at 2 and 4 months old. There are two coprimary endpoints: (1) seroconversion from baseline serum anti-rotavirus immunoglobulin A (IgA) titre <20 U/mL prior to an additional dose of Rotarix/placebo to serum anti-rotavirus IgA titre >20 U/mL following the administration of the additional dose of Rotarix/placebo and (2) time from randomisation to medical attendance (up to age 36 months old) for which the primary reason is acute gastroenteritis/diarrhoea. Secondary endpoints include the change in anti-rotavirus IgA log titre, time to hospitalisation for all-cause diarrhoea and for rotavirus-confirmed gastroenteritis/diarrhoea, and rotavirus notification. Analysis will be based on Bayesian inference with adaptive sample size. ETHICS, REGISTRATION AND DISSEMINATION: Ethics approval has been granted by Central Australian Human Research Ethics Committee (HREC-16-426) and Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC-2016-2658). Study investigators will ensure the trial is conducted in accordance with the principles of the Declaration of Helsinki and with the ICH Guidelines for Good Clinical Practice. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. The trial is registered with Clinicaltrials.gov (NCT02941107) and important modifications to this protocol will be updated. TRIAL REGISTRATION NUMBER: NCT02941107; Pre-results.


Asunto(s)
Gastroenteritis/prevención & control , Grupo de Ascendencia Oceánica , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Administración Oral , Anticuerpos Antivirales/sangre , Australia , Teorema de Bayes , Ensayos Clínicos Fase IV como Asunto , Diarrea/prevención & control , Método Doble Ciego , Gastroenteritis/virología , Humanos , Programas de Inmunización , Inmunoglobulina A/sangre , Lactante , Ensayos Clínicos Controlados Aleatorios como Asunto , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología
17.
Cardiovasc Diabetol ; 18(1): 149, 2019 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-31706300

RESUMEN

BACKGROUND: Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). METHODS: In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. RESULTS: This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. CONCLUSIONS: Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Aterosclerosis/tratamiento farmacológico , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Enfermedad Coronaria/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Inhibidores de Serina Proteinasa/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticolesterolemiantes/efectos adversos , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Aterosclerosis/epidemiología , Biomarcadores/sangre , Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Fase IV como Asunto , Enfermedad Coronaria/sangre , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/epidemiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Quimioterapia Combinada , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/epidemiología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Estudios Multicéntricos como Asunto , Proproteína Convertasa 9/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Inhibidores de Serina Proteinasa/efectos adversos , Factores de Tiempo , Resultado del Tratamiento
18.
BMJ Open ; 9(11): e033718, 2019 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-31685516

RESUMEN

INTRODUCTION: Resistant Gram-positive organisms, such as methicillin-resistant staphylococci, account for a significant proportion of infections following joint replacement surgery. Current surgical antimicrobial prophylaxis guidelines recommend the use of first-generation or second-generation cephalosporin antibiotics, such as cefazolin. Cefazolin, however, does not prevent infections due to these resistant organisms; therefore, new prevention strategies need to be examined. One proposed strategy is to combine a glycopeptide antibiotic with cefazolin for prophylaxis. The clinical benefit and cost-effectiveness of this combination therapy compared with usual therapy, however, have not been established. METHODS AND ANALYSIS: This randomised, double-blind, parallel, superiority, placebo-controlled, phase 4 trial will compare the incidence of all surgical site infections (SSIs) including superficial, deep and organ/space (prosthetic joint) infections, safety and cost-effectiveness of surgical prophylaxis with cefazolin plus vancomycin to that with cefazolin plus placebo. The study will be performed in patients undergoing joint replacement surgery. In the microbiological sub-studies, we will examine the incidence of SSIs in participants with preoperative staphylococci colonisation (Sub-Study 1) and incidence of VRE acquisition (Sub-Study 2). The trial will recruit 4450 participants over a 4-year period across 13 orthopaedic centres in Australia. The primary outcome is the incidence of SSI at 90 days post index surgery. Secondary outcomes include the incidence of SSI according to joint and microorganism and other healthcare associated infections. Safety endpoints include the incidence of acute kidney injury, hypersensitivity reactions and all-cause mortality. The primary and secondary analysis will be a modified intention-to-treat analysis consisting of all randomised participants who undergo eligible surgery. We will also perform a per-protocol analysis. ETHICS AND DISSEMINATION: The study protocol was reviewed and approved by The Alfred Hospital Human Research Ethics Committee (HREC/18/Alfred/102) on 9 July 2018. Study findings will be disseminated in the printed media, and learnt forums. TRIAL REGISTRATION NUMBER: ACTRN12618000642280.


Asunto(s)
Antibacterianos/uso terapéutico , Profilaxis Antibiótica/efectos adversos , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas/prevención & control , Infección de la Herida Quirúrgica/prevención & control , Artroplastia/mortalidad , Australia , Causas de Muerte , Cefazolina/uso terapéutico , Ensayos Clínicos Fase IV como Asunto , Método Doble Ciego , Humanos , Estudios Multicéntricos como Asunto , Complicaciones Posoperatorias/microbiología , Complicaciones Posoperatorias/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Infecciones Estafilocócicas/microbiología , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/microbiología , Vancomicina/uso terapéutico
19.
Cardiovasc Drugs Ther ; 33(6): 701-710, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31745687

RESUMEN

BACKGROUND: Whether four direct oral anticoagulants (DOACs) are superior to warfarin among Asians with non-valvular atrial fibrillation (NVAF) remains unclear in the real-world setting. METHODS: We searched PubMed and Medline + Journals@Ovid + EMBASE from September 17, 2009 to May 4, 2019 to perform a systematic review and meta-analysis of all observational real-world studies comparing four DOACs with warfarin specifically focused on Asian patients with NVAF. RESULTS: From the original 212 results retrieved, 18 studies were included in the meta-analysis. Overall, DOACs were associated with lower risks of thromboembolism (hazard ratio; [95% confidence interval], 0.70; [0.63-0.78]), acute myocardial infarction (0.67; [0.57-0.79]), all-cause mortality (0.62; [0.56-0.69]), major bleeding (0.59; [0.50-0.69]), intracranial hemorrhage (0.50; [0.40-0.62]), gastrointestinal bleeding (0.66; [0.46-0.95]), and any bleeding (0.82; [0.73-0.92]) than warfarin. There was statistic heterogeneity between DOACs for the risks of thromboembolism (P interaction = 0.03) and acute myocardial infarction (P interaction = 0.007) when compared to warfarin. However, all DOACs showed lower risks of thromboembolism and acute myocardial infarction than warfarin when pooling studies that compared individual DOAC with warfarin. With regard to the other outcomes when compared to warfarin, there was no statistical heterogeneity between DOACs. In addition, the effectiveness and safety of four DOACs versus warfarin persisted in the subgroups of either standard-dose or low-dose DOACs. CONCLUSIONS: The meta-analysis shows that the DOACs had greater effectiveness and safety compared to warfarin in real-world practice for stroke prevention, among Asian patients with NVAF.


Asunto(s)
Anticoagulantes/administración & dosificación , Antitrombinas/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Inhibidores del Factor Xa/administración & dosificación , Accidente Cerebrovascular/prevención & control , Warfarina/administración & dosificación , Administración Oral , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Antitrombinas/efectos adversos , Grupo de Ascendencia Continental Asiática , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/etnología , Fibrilación Atrial/mortalidad , Causas de Muerte , Ensayos Clínicos Fase IV como Asunto , Inhibidores del Factor Xa/efectos adversos , Femenino , Hemorragia/inducido químicamente , Hemorragia/etnología , Hemorragia/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etnología , Accidente Cerebrovascular/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Warfarina/efectos adversos
20.
Artif Intell Med ; 100: 101703, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31607342

RESUMEN

OBJECTIVES: We develop a fuzzy evaluation model that provides managers at different responsibility levels in pharmaceutical laboratories with a rich picture of their innovation risk as well as that of competitors. This would help them take better strategic decisions around the management of their present and future portfolio of clinical trials in an uncertain environment. Through three structured fuzzy inference systems (FISs), the model evaluates the overall innovation risk of the laboratories by capturing the financial and pipeline sides of the risk. METHODS AND MATERIALS: Three FISs, based on the Mamdani model, determine the level of innovation risk of large pharmaceutical laboratories according to their strategic choices. Two subsystems measure different aspects of innovation risk while the third one builds on the results of the previous two. In all of them, both the partitions of the variables and the rules of the knowledge base are agreed through an innovative 2-tuple-based method. With the aid of experts, we have embedded knowledge into the FIS and later validated the model. RESULTS: In an empirical application of the proposed methodology, we evaluate a sample of 31 large pharmaceutical laboratories in the period 2008-2013. Depending on the relative weight of the two subsystems in the first layer (capturing the financial and the pipeline sides of innovation risk), we estimate the overall risk. Comparisons across laboratories are made and graphical surfaces are analyzed in order to interpret our results. We have also run regressions to better understand the implications of our results. CONCLUSIONS: The main contribution of this work is the development of an innovative fuzzy evaluation model that is useful for analyzing the innovation risk characteristics of large pharmaceutical laboratories given their strategic choices. The methodology is valid for carrying out a systematic analysis of the potential for developing new drugs over time and in a stable manner while managing the risks involved. We provide all the necessary tools and datasets to facilitate the replication of our system, which also may be easily applied to other settings.


Asunto(s)
Toma de Decisiones en la Organización , Industria Farmacéutica , Lógica Difusa , Invenciones , Medición de Riesgo , Planificación Estratégica , Ensayos Clínicos Fase I como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase IV como Asunto/estadística & datos numéricos , Aprobación de Drogas/estadística & datos numéricos , Industria Farmacéutica/métodos , Humanos , Modelos Estadísticos , Probabilidad , Investigación
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