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1.
Trials ; 21(1): 1014, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33302976

RESUMO

OBJECTIVES: SARS-Cov-2 virus preferentially binds to the Angiotensin Converting Enzyme 2 (ACE2) on alveolar epithelial type II cells, initiating an inflammatory response and tissue damage which may impair surfactant synthesis contributing to alveolar collapse, worsening hypoxia and leading to respiratory failure. The objective of this study is to evaluate the feasibility, safety and efficacy of nebulised surfactant in COVID-19 adult patients requiring mechanical ventilation for respiratory failure. TRIAL DESIGN: This study is a dose-escalating randomized open-label clinical trial of 20 COVID-19 patients. PARTICIPANTS: This study is conducted in two centres: University Hospital Southampton and University College London Hospitals. Eligible participants are aged ≥18, hospitalised with COVID-19 (confirmed by PCR), who require endotracheal intubation and are enrolled within 24 hours of mechanical ventilation. For patients unable to consent, assent is obtained from a personal legal representative (PerLR) or professional legal representative (ProfLR) prior to enrolment. The following are exclusion criteria: imminent expected death within 24 hours; specific contraindications to surfactant administration (e.g. known allergy, pneumothorax, pulmonary hemorrhage); known or suspected pregnancy; stage 4 chronic kidney disease or requiring dialysis (i.e., eGFR < 30); liver failure (Child-Pugh Class C); anticipated transfer to another hospital, which is not a study site, within 72 hours; current or recent (within 1 month) participation in another study that, in the opinion of the investigator, would prevent enrollment for safety reasons; and declined consent or assent. INTERVENTION AND COMPARATOR: Intervention: The study is based on an investigational drug/device combination product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13% phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5% cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lyso-phosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an investigational device based on the Aerogen® Solo vibrating mesh nebulizer. The timing and escalation dosing plans for the surfactant are as follows. Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and 30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention. Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240 mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls. 2 controls with no placebo intervention. The trial steering committee, advised by the data monitoring committee, will review trial progression and dose escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached) based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns. Comparator: No placebo intervention. All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated patients and all other treatments will be left to the discretion of the attending physician. MAIN OUTCOMES: The co-primary outcome is the improvement in oxygenation (PaO2/FiO2 ratio) and pulmonary ventilation (Ventilation Index (VI), where VI = [RR x (PIP - PEEP) × PaCO2]/1000) at 48 hours after study initiation. The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance, change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28. Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR, surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and cytokine) in plasma and DTAS, and blood oxidative stress markers. RANDOMISATION: After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials, FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting centre with a unique subject identifier specific to that centre. BLINDING (MASKING): This is an open-labelled unblinded study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The total sample size is 20 COVID-19 mechanically ventilated patients (12 intervention; 8 control). TRIAL STATUS: Current protocol version is V2 dated 5th of June 2020. The recruitment is currently ongoing and started on the 14th of October 2020. The anticipated study completion date is November 2021. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) 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. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

2.
JAMA Oncol ; 6(8): 1256-1264, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32672795

RESUMO

Importance: The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established. Objective: To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab. Design, Setting, and Participants: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had received pembrolizumab. Interventions: Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks. Main Outcomes and Measures: End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy. Results: The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively. Conclusions and Relevance: Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.

3.
Pharmacogenomics ; 20(9): 631-641, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31250727

RESUMO

Aim: To evaluate the effect of SLCO1B1 genetic variants on grazoprevir pharmacokinetics and efficacy. Methods: A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Results: Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of grazoprevir area under curve (AUC)0-24 were: rs4149056 (risk allele C), one copy, 1.13 (1.06-1.21), two copies, 1.43 (1.16-1.77); and rs11045819 (risk allele A), one copy, 0.93 (0.87-1.00); two copies, 0.78 (0.61-1.00). The rs2306283 variant was not associated with grazoprevir exposure. None of the SLCO1B1 variants were associated with sustained virologic response. Conclusion: Genetic variants in SLCO1B1 were associated with modest changes in grazoprevir pharmacokinetics, but not with meaningful differences in efficacy.


Assuntos
Antivirais/sangue , Benzofuranos/sangue , Hepatite C/tratamento farmacológico , Imidazóis/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Polimorfismo de Nucleotídeo Único , Quinoxalinas/sangue , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Benzofuranos/administração & dosagem , Benzofuranos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Combinação de Medicamentos , Feminino , Hepacivirus/genética , Hepatite C/genética , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Quinoxalinas/administração & dosagem , Quinoxalinas/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
4.
Nat Med ; 25(3): 454-461, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804515

RESUMO

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos , Quimioterapia Adjuvante , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/patologia , Transcriptoma , Evasão Tumoral
5.
Science ; 362(6411)2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30309915

RESUMO

Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Terapia de Alvo Molecular/métodos , Neoplasias/genética , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pontos de Checagem do Ciclo Celular , Marcadores Genéticos , Humanos , Imunoterapia , Inflamação/genética , Mutação , Linfócitos T/imunologia , Transcriptoma , Carga Tumoral/genética
6.
Lancet Oncol ; 19(3): 347-355, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29395863

RESUMO

BACKGROUND: Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma. METHODS: We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis. FINDINGS: 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity. INTERPRETATION: Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential. FUNDING: Merck & Co.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , District of Columbia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Timoma/imunologia , Timoma/mortalidade , Timoma/patologia , Neoplasias do Timo/imunologia , Neoplasias do Timo/mortalidade , Neoplasias do Timo/patologia , Fatores de Tempo , Resultado do Tratamento
7.
Metabolism ; 71: 202-212, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28521874

RESUMO

BACKGROUND: SREBP cleavage-activating protein (SCAP) is a cholesterol binding endoplasmic reticulum (ER) membrane protein that is required to activate SREBP transcription factors. SREBPs regulate genes involved in lipid biosynthesis. They also influence lipid clearance by modulating the expression of LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Inhibiting SCAP decreases circulating PCSK9, triglycerides (TG), and LDL-cholesterol (LDL-C), both in vitro and in vivo. Type 2 diabetics with dyslipidemia are at high risk for cardiovascular diseases. These patients present a unique pathophysiological lipid profile characterized by moderately elevated LDL-C, elevated TG and reduced HDL-cholesterol (HDL-C). The spontaneous dysmetabolic rhesus monkey model (DysMet RhM) recapitulates this human dyslipidemia and therefore is an attractive preclinical model to evaluate SCAP inhibition as a therapy for this disease population. The objective to of this study was to assess the effect of SCAP inhibition on the lipid profile of DysMet RhM. METHOD: We assessed the effect of inhibiting hepatic SCAP on the lipid profile of DysMet RhM using an siRNA encapsulated lipid nanoparticle (siRNA-LNP). RESULTS: The SCAP siRNA-LNP significantly reduced LDL-C, PCSK9 and TG in DysMet RhM; LDL-C was reduced by ≥20%, circulating PCSK9 by 30-40% and TG by >25%. These changes by the SCAP siRNA-LNP agree with the predicted effect of SCAP inhibition and reduced SREBP tone on these endpoints. CONCLUSION: These data demonstrate that a SCAP siRNA-LNP improved the lipid profile in a clinically relevant preclinical disease model and provide evidence for SCAP inhibition as a therapy for diabetic dyslipidemic patients.


Assuntos
Dislipidemias/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA Interferente Pequeno/uso terapêutico , Animais , Biomarcadores/sangue , Colesterol/sangue , Feminino , Lipídeos/sangue , Fígado/metabolismo , Macaca mulatta , Masculino , Nanopartículas , Ácido Palmítico/sangue , Pró-Proteína Convertase 9/sangue , RNA Interferente Pequeno/administração & dosagem , Triglicerídeos/metabolismo
8.
Clin Trials ; 13(1): 57-65, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26768568

RESUMO

Starting in December 2013, West Africa was overwhelmed with the deadliest outbreak of Ebola virus known to date, resulting in more than 27,500 cases and 11,000 deaths. In response to the epidemic, development of a heterologous prime-boost vaccine regimen was accelerated and involved preparation of a phase 3 effectiveness study. While individually randomized controlled trials are widely acknowledged as the gold standard for demonstrating the efficacy of a candidate vaccine, there was considerable debate on the ethical appropriateness of these designs in the context of an epidemic. A suitable phase 3 trial must convincingly ensure unbiased evaluation with sufficient statistical power. In addition, efficient evaluation of a vaccine candidate is required so that an effective vaccine can be immediately disseminated. This manuscript aims to present the statistical and modeling considerations, design rationale and challenges encountered due to the emergent, epidemic setting that led to the selection of a cluster-randomized phase 3 study design under field conditions.


Assuntos
Ensaios Clínicos Fase III como Assunto/métodos , Vacinas contra Ebola , Doença pelo Vírus Ebola/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , África Ocidental/epidemiologia , Simulação por Computador , Interpretação Estatística de Dados , Surtos de Doenças , Doença pelo Vírus Ebola/epidemiologia , Humanos , Modelos Biológicos , Resultado do Tratamento
9.
Artigo em Inglês | MEDLINE | ID: mdl-26557261

RESUMO

BACKGROUND: Allergen-induced late airway response offers important pharmacodynamic targets, including T helper 2 (TH2) biomarkers. However, detection of inflammatory markers has been limited in dithiothreitol-processed sputum. OBJECTIVES: To test whether allergen-induced TH2 inflammatory markers can be reproducibly quantified by sensitive detection techniques in ultracentrifuged sputum and the effect of fluticasone (FP) on these endpoints. METHODS: Thirteen allergic asthmatics with dual allergen-induced airway responses, documented during a single-blind placebo run-in period, participated in a double-blind, two-period crossover study. Each period consisted of three consecutive days, separated by ≥3 weeks. Following randomization, subjects inhaled FP (500 µg bid, five doses total) or placebo. On Day 2 in each study period, allergen challenge was performed and airway response measured by forced expiratory volume in 1 sec (FEV1) until 7 h post-challenge. Sputum was induced 24 h pre-allergen and 7 and 24 h post-allergen. Sputum samples were split into two portions: TH2 biomarkers were quantified by Meso Scale multiplex platform following ultracentrifugation, and cell differentials were counted on Giemsa-May-Grünwald-stained cytospins. Allergen-induced changes in inflammatory endpoints were compared between FP and placebo using a mixed model ANCOVA. RESULTS: Inhaled allergen induced dual airway responses in all subjects during both placebo periods with reproducible late asthmatic response (LAR) and increased sputum inflammatory biomarkers (IL-2, IL-4, IL-13, and eotaxin-1) and eosinophil counts. FP effectively blunted both the LAR and the inflammatory biomarkers. CONCLUSIONS: Combining novel, sensitive quantification methods with ultracentrifugation allows reproducible quantification of sputum biomarkers following allergen challenge, reversed by FP. This approach allows non-invasive identification of pharmacodynamic targets for anti-asthma therapies.

10.
J Sleep Res ; 24(1): 66-73, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25113527

RESUMO

Non-nucleoside reverse transcriptase inhibitors are important antiretroviral agents for the treatment of human immunodeficiency virus. Some non-nucleoside reverse transcriptase inhibitors, in particular efavirenz, have prominent effects on sleep, cognition and psychiatric variables that limit their tolerability. To avoid confounds due to drug-drug and drug-disease interactions, we assessed the effects of efavirenz in healthy volunteers on sleep, cognition and psychological endpoints during the first week of treatment. Forty healthy male subjects were randomized to receive placebo or efavirenz 600 mg nightly for 7 days after completion of a 3-day placebo run-in period. Treatment with efavirenz was associated with reduced time to sleep onset in the Maintenance of Wakefulness Test, an increase in non-rapid eye movement sleep, a large exposure-related decrease in sigma band spectral density and sleep spindle density during non-rapid eye movement sleep, and reduced performance on an attention switching task. Because efavirenz has been shown to have serotonin 2A receptor partial-agonist properties, we reasoned that antagonism of serotonin 2A receptor signalling in the thalamic reticular nucleus, which generates sleep spindles and promotes attention, may be responsible. Consistent with predictions, treatment of healthy volunteers with a single dose of a serotonin 2A receptor antagonist was found to significantly suppress sigma band spectral density in an exposure-related manner and modulated the overall spectral profile in a manner highly similar to that observed with efavirenz, consistent with the notion that efavirenz exhibits serotonin 2A receptor partial-agonist pharmacology in humans.


Assuntos
Benzoxazinas/farmacologia , Sono/efeitos dos fármacos , Sono/fisiologia , Adulto , Alquinos , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Atenção/efeitos dos fármacos , Atenção/fisiologia , Benzoxazinas/efeitos adversos , Cognição/efeitos dos fármacos , Cognição/fisiologia , Ciclopropanos , Agonismo Parcial de Drogas , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Receptor 5-HT2A de Serotonina/metabolismo , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Vigília/efeitos dos fármacos , Vigília/fisiologia , Adulto Jovem
11.
Open Forum Infect Dis ; 1(1): ofu016, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25734089

RESUMO

The immunogenicity results from 3 phase I trials of the Merck DNA human immunodeficiency virus (HIV) vaccine have previously been reported. Because preventive DNA vaccine strategies continue to be leveraged for diverse infections, the safety and tolerability results from these studies can inform the field moving forward, particularly regarding adverse reactions and adjuvants. No serious vaccine-related adverse events were reported during the 3-dose priming phase. Pain at the injection site was more common with adjuvanted formulations than with the phosphate-buffered saline diluent alone. Febrile reactions were usually low grade. Although the AlPO4 or CRL1005 adjuvants used in these studies did not significantly enhance the immunogenicity of the DNA vaccine, adverse events were numerically more common with adjuvanted formulations than without adjuvants.

12.
J Am Coll Cardiol ; 62(10): 909-17, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-23727083

RESUMO

OBJECTIVES: The study sought to test whether high-dose statin treatment would result in greater reductions in plaque inflammation than low-dose statins, using fluorodeoxyglucose-positron emission tomography/computed tomographic imaging (FDG-PET/CT). BACKGROUND: Intensification of statin therapy reduces major cardiovascular events. METHODS: Adults with risk factors or with established atherosclerosis, who were not taking high-dose statins (n = 83), were randomized to atorvastatin 10 versus 80 mg in a double-blind, multicenter trial. FDG-PET/CT imaging of the ascending thoracic aorta and carotid arteries was performed at baseline, 4, and 12 weeks after randomization and target-to-background ratio (TBR) of FDG uptake within the artery wall was assessed while blinded to time points and treatment. RESULTS: Sixty-seven subjects completed the study, providing imaging data for analysis. At 12 weeks, inflammation (TBR) in the index vessel was significantly reduced from baseline with atorvastatin 80 mg (% reduction [95% confidence interval]: 14.42% [8.7% to 19.8%]; p < 0.001), but not atorvastatin 10 mg (% reduction: 4.2% [-2.3% to 10.4%]; p > 0.1). Atorvastatin 80 mg resulted in significant additional relative reductions in TBR versus atorvastatin 10 mg (10.6% [2.2% to 18.3%]; p = 0.01) at week 12. Reductions from baseline in TBR were seen as early as 4 weeks after randomization with atorvastatin 10 mg (6.4% reduction, p < 0.05) and 80 mg (12.5% reduction, p < 0.001). Changes in TBR did not correlate with lipid profile changes. CONCLUSIONS: Statin therapy produced significant rapid dose-dependent reductions in FDG uptake that may represent changes in atherosclerotic plaque inflammation. FDG-PET imaging may be useful in detecting early treatment effects in patients at risk or with established atherosclerosis.


Assuntos
Aorta Torácica/diagnóstico por imagem , Aterosclerose/tratamento farmacológico , Artérias Carótidas/diagnóstico por imagem , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Placa Aterosclerótica/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta Torácica/patologia , Aterosclerose/diagnóstico por imagem , Atorvastatina , Artérias Carótidas/patologia , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Fluordesoxiglucose F18 , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inflamação/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Placa Aterosclerótica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Pirróis/administração & dosagem , Resultado do Tratamento
13.
Biometrics ; 68(2): 617-27, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22059475

RESUMO

Biomarkers play an increasing role in the clinical development of new therapeutics. Earlier clinical decisions facilitated by biomarkers can lead to reduced costs and duration of drug development. Associations between biomarkers and clinical endpoints are often viewed as initial evidence supporting the intended purpose. As a result, even though it is widely understood that correlation is not proof of a causal relationship, correlation continues to be used as a metric for biomarker qualification in practice. In this article, we introduce a causal correlation framework where two different types of correlations are defined at the individual level. We show that the correlation estimate is a composite of different components, and needs to be interpreted with caution when used for biomarker qualification to avoid misleading conclusions. Otherwise, a significant correlation can be concluded even in the absence of a true underlying association. We also show how the causal quantities of interest are testable in a crossover design and provide discussion on the challenges that exist in a parallel group setting.


Assuntos
Biomarcadores/análise , Biometria/métodos , Causalidade , Simulação por Computador , Humanos , Modelos Estatísticos , Terapêutica/estatística & dados numéricos
14.
Stat Med ; 28(20): 2509-30, 2009 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-19610129

RESUMO

In randomized clinical trials, a pre-treatment measurement is often taken at baseline, and post-treatment effects are measured at several time points post-baseline, say t=1, ..., T. At the end of the trial, it is of interest to assess the treatment effect based on the mean change from baseline at the last time point T. We consider statistical methods for (i) a point estimate and 95 per cent confidence interval for the mean change from baseline at time T for each treatment group, and (ii) a p-value and 95 per cent confidence interval for the between-group difference in the mean change from baseline. The manner in which the baseline responses are used in the analysis influences both the accuracy and the efficiency of items (i) and (ii). In this paper, we will consider the ANCOVA approach with change from baseline as a dependent variable and compare that with a constrained longitudinal data analysis (cLDA) model proposed by Liang and Zeger (Sankhya: Indian J. Stat. (Ser B) 2000; 62:134-148), in which the baseline is modeled as a dependent variable in conjunction with the constraint of a common baseline mean across the treatment groups. Some drawbacks of the ANCOVA model and potential advantages of the cLDA approach are discussed and illustrated using numerical simulations.


Assuntos
Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do Tratamento , Algoritmos , Análise de Variância , Anticorpos/sangue , Anticorpos/imunologia , Simulação por Computador , Intervalos de Confiança , Humanos , Funções Verossimilhança , Projetos de Pesquisa , Vacinas/administração & dosagem , Vacinas/imunologia
15.
Mol Ther ; 17(5): 922-8, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19277016

RESUMO

Immunotherapy against infectious agents and malignant tumors requires efficient priming of effector cells through direct expression and/or efficient cross-presentation of antigens by antigen-presenting cells. Electroporation is a new procedure aimed at transiently increasing cell membrane permeability and direct delivery of antigen or antigen-encoding nucleic acids inside targeted cells. We evaluated the tolerability including compliance with repeated electroporation treatments using MedPulser DDS in 24 healthy adults. Pain severity was evaluated at time of electroporation treatment, and at 1, 5, 10, and 20 minutes, and 24 hours thereafter, using two clinically validated questionnaires: McGill Pain Questionnaire (MPQ) (Present Pain Intensity) and Brief Pain Inventory (BPI). Electroporation treatments were generally well tolerated. Twenty-two out of 24 subjects returned for the second electroporation treatment 14 days after first treatment. Only two subjects reported a treatment-related systemic adverse experience following either electroporation application. For both pain assessment tools, maximum pain and/or discomfort were mostly reported immediately (within 5 minutes) after electroporation; Furthermore, no difference was observed when comparing peak-pain scores after first and second electroporation treatments. This study supports the clinical application of MedPulser DDS for the improvement of antigen-induced immune responses for prophylactic or therapeutic vaccines, especially in gene-based therapies for cancer.


Assuntos
Eletroporação/instrumentação , Terapia Genética/instrumentação , Terapia Genética/métodos , Adolescente , Adulto , Eletroporação/métodos , Feminino , Humanos , Imunoterapia , Masculino , Medição da Dor , Adulto Jovem
16.
J Pharm Sci ; 98(11): 3987-96, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19283757

RESUMO

Quantitation of residual hydrogen peroxide (H(2)O(2)) and evaluation of the impact on product stability is necessary as unwanted H(2)O(2) can potentially be introduced during the manufacturing of pharmaceuticals, biologics, and vaccines. A sensitive and convenient microplate-based method with fluorescence detection for H(2)O(2) quantitation was recently reported (Towne et al., 2004, Anal Biochem 334: 290-296). This method was found to be highly robust and reproducible, with a level of detection of 0.015 ppm and a level of quantitation of 0.025 ppm (in water). The relatively small sample requirements and amenability for automation make this assay an attractive tool for detecting residual H(2)O(2) levels. Without additional manipulation, the assay can be conducted on heterogeneous solutions with significant degree of turbidity, such as the presence of suspensions or aluminum-containing adjuvants. The quantitation of H(2)O(2) and its decomposition kinetics was also studied in presence of two common vaccine preservatives (thimerosal and phenol) and eight commonly used excipients (polyols). Over time, there is a distinct, temperature dependent decrease in H(2)O(2) recovered in thimerosal and phenol containing samples versus non-preservative containing controls. Based on the half-life of spiked H(2)O(2), the decay rates in eight polyols tested were found to be: ribose > sucrose > (glycerol, glucose, lactose, mannitol, sorbitol, and xylose).


Assuntos
Excipientes/análise , Peróxido de Hidrogênio/análise , Fenol/análise , Conservantes Farmacêuticos/análise , Timerosal/análise , Corantes/farmacologia , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Peróxido de Hidrogênio/farmacologia , Concentração de Íons de Hidrogênio , Cinética , Oxazinas/farmacologia , Oxirredução , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Temperatura , Água/química
17.
Clin Infect Dis ; 47(12): 1593-9, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18990058

RESUMO

BACKGROUND: We analyzed human immunodeficiency virus (HIV) seroresponses from 3 phase I HIV-1 vaccine trials to assess the frequency of vaccine-induced seroconversion. METHODS: HIV-1 and HIV-2 enzyme-linked immunosorbent assay (ELISA) was performed during trials of adenovirus type 5 (Ad5)-vectored clade B HIV-1 monovalent gag and trivalent gag/pol/nef vaccines given to HIV-seronegative adults. Doses were administered at day 1, week 4, and week 26. Results were analyzed by vaccine formulation and dose and were stratified by baseline Ad5 titer. ELISA-positive samples were reflexively tested by Western blotting. RESULTS: Overall, 165 (41%) of 406 evaluable vaccine recipients had positive ELISA results but negative PCR results by week 78. Seroconversion rates were directly related to vaccine dose, were inversely related to baseline Ad5 titer, and were unaffected by vaccine valency. One hundred (89%) of 113 evaluable patients with low baseline Ad5 antibody titers (or=1 dose of vaccine with >or=1 x 10(10) gag-containing Ad5 particles per dose experienced seroconversion. Of 163 vaccine recipients who had positive ELISA results and available Western blot results, 150 (92%) had indeterminate results of Western blot, typically involving bands at p24, p40, and/or p55. Thirteen uninfected patients (8%) had equivocally positive Western blot results, usually because of an additional weak glycoprotein 41 band. Env-specific enzyme immunoassay results were falsely positive for 2 uninfected vaccine recipients. CONCLUSIONS: Positive ELISA results were similarly common for monovalent and trivalent vaccine recipients. Vaccine dose and baseline Ad5 immunity were major determinants of vaccine-induced seroconversion rates. Corresponding Western blots characteristically showed bands directed only at Gag proteins, which helped to distinguish HIV-uninfected vaccine recipients who experienced seroconversion from true HIV-infected patients. If available, an enzyme immunoassay exclusively targeting proteins not expressed by the vaccine should be the screening test of first choice for vaccine recipients.


Assuntos
Vacinas contra a AIDS/imunologia , Soropositividade para HIV , HIV-1/imunologia , Vacinas contra a AIDS/administração & dosagem , Adenoviridae/genética , Adolescente , Adulto , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Vetores Genéticos , Anticorpos Anti-HIV/sangue , Humanos , Imunização Secundária , Masculino , Pessoa de Meia-Idade
18.
Lancet ; 372(9653): 1881-1893, 2008 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-19012954

RESUMO

BACKGROUND: Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. METHODS: We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. FINDINGS: In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men. INTERPRETATION: This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.


Assuntos
Vacinas contra a AIDS/uso terapêutico , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Adolescente , Adulto , Método Duplo-Cego , Feminino , Antígenos HIV/classificação , Antígenos HIV/efeitos dos fármacos , Antígenos HIV/isolamento & purificação , Infecções por HIV/imunologia , Humanos , Imunidade Celular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Comportamento Sexual , Adulto Jovem
19.
Clin Infect Dis ; 46(11): 1769-81, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18433307

RESUMO

BACKGROUND: The safety and immunogenicity of the MRK adenovirus type 5 human immunodeficiency virus type 1 clade B gag/pol/nef vaccine, a replication-incompetent adenovirus type 5-vectored vaccine designed to elicit cell-mediated immunity against conserved human immunodeficiency virus proteins, was assessed in a phase 1 trial. METHODS: Healthy adults not infected with human immunodeficiency virus were enrolled in a multicenter, dose-escalating, blind, placebo-controlled study to evaluate a 3-dose homologous prime-boost regimen of the trivalent MRK adenovirus type 5 human immunodeficiency virus type 1 vaccine containing from 3 x 10(6) to 1 x 10(11) viral particles per 1-mL dose administered on day 1, during week 4 and during week 26. Adverse events were recorded for 29 days after each intradeltoid injection. The primary immunogenicity end point was the proportion of study participants with a positive unfractionated Gag-, Pol-, or Nef-specific interferon-gamma enzyme-linked immunosorbent spot response measured 4 weeks after administration of the last dose. RESULTS: Of 259 randomized individuals, 257 (99%) received > or = 1 dose of vaccine or placebo and were included in the safety analyses. Enzyme-linked immunosorbent spot results were available for 217 study participants (84%) at week 30. No serious vaccine-related adverse events occurred. No study participant discontinued participation because of vaccine-related adverse events. The frequency of injection-site reactions was dose dependent. Vaccine doses of > or = 3 x 10(9) viral particles elicited positive enzyme-linked immunosorbent spot responses to > or = 1 vaccine component in > 60% of recipients. High baseline antibody titers against adenovirus type 5 diminished enzyme-linked immunosorbent spot responses at all doses except the 3 x 10(10) viral particle dose. CONCLUSIONS: The vaccine was generally well tolerated and induced cell-mediated immune responses against human immunodeficiency virus type 1 peptides in most healthy adults. Despite these findings, vaccination in a proof-of-concept trial with use of this vaccine was discontinued because of lack of efficacy.


Assuntos
Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vacinas contra a AIDS/administração & dosagem , Adenoviridae , Adulto , Feminino , Proteínas de Fusão gag-pol/imunologia , Genes gag , Genes pol , Anticorpos Anti-HIV/biossíntese , Infecções por HIV/imunologia , HIV-1/genética , Humanos , Masculino , Segurança , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Vacinas de DNA/imunologia
20.
AIDS Res Hum Retroviruses ; 23(1): 86-92, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17263637

RESUMO

Quantitative analysis of cell-mediated immune responses induced by candidate HIV vaccines requires robust procedures for collecting and processing human peripheral mononuclear blood cells (PBMCs). We evaluated several parameters in order to optimize a sample handling process that would be suitable for a multicenter clinical trial. Among the findings, systematic increases in the magnitude of IFN-gamma ELISpot responses were observed when the time from blood collection to PBMC freezing was reduced to <12 h. By implementing these improvements within an ongoing clinical trial, the estimated immunologic response rates to an adenovirus- based HIV vaccine increased by more than 20 percentage points to approximately 80% of the vaccine recipients against any of the vaccine antigens and the average levels of T cell response improved more than 3-fold. These studies establish the importance of optimal conditions for PBMC collection and handling to the success of a clinical development program.


Assuntos
Vacinas contra a AIDS/imunologia , Leucócitos Mononucleares/imunologia , Manejo de Espécimes , Vacinas contra a AIDS/uso terapêutico , Adenoviridae/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Ensaios Clínicos como Assunto , Criopreservação , Ensaio de Imunoadsorção Enzimática , Infecções por HIV/prevenção & controle , Soronegatividade para HIV , Humanos , Imunidade Celular , Interferon gama/imunologia , Linfócitos T/imunologia , Fatores de Tempo
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