Premature Discontinuation of Randomized Trials in Critical and Emergency Care: A Retrospective Cohort Study.

OBJECTIVES: Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. DESIGN: Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. SETTING: Randomized clinical trials involving patients in an acute or nonacute care setting. SUBJECTS AND INTERVENTIONS: We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. MEASUREMENTS AND MAIN RESULTS: Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. CONCLUSIONS: Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.

Pharmacométrie de la ropivacaïne suivant l’anesthésie locorégionale chez les patients orthopédiques : caractérisation de l’intensité et de la durée du bloc sensitif

Introduction & Objectifs : Pour assurer l’analgésie postopératoire, l’anesthésiste dispose, en plus des différentes classes de médicaments administrés par voie orale ou intraveineuse, de diverses techniques pour bloquer l’influx nerveux douloureux en administrant les anesthésiques locaux (AL) de manière centrale ou périphérique. La ropivacaïne (ROP), un AL à longue durée d’action, est un médicament de première intention partout dans le monde, en raison de sa grande efficacité et de son faible risque de toxicité. Contrairement à certains pays, la ROP n'est toujours pas indiquée au Canada pour la rachianesthésie (bloc central) en raison d'un manque de données probantes. Jusqu'à présent, les efforts de recherche ont essentiellement porté sur la sécurité ainsi que sur la durée d’action du médicament lorsqu’administré par voie spinale. De plus, les doses optimales de ROP pour l’anesthésie régionale périphérique ne sont pas encore précisément connues. La posologie devrait être adaptée au site d’administration ainsi qu’à l’intensité et la durée du stimulus produit par la chirurgie. Ultimement, cela permettrait aux cliniciens d’identifier le régime optimal en fonction des facteurs démographiques qui pourraient affecter la pharmacocinétique (PK) et la pharmacodynamie (PD) de l’AL (objectif global de ces travaux). Validation de la Méthode Analytique Manuscrit 1 : Une méthode analytique spécifique et sensible permettant de déterminer les concentrations plasmatiques de ROP a d’abord été optimisée et validée. Validation du Biomarqueur Manuscrit 2 : Nous avons ensuite mis au point et évalué la fiabilité d’une méthode quantitative basée sur la mesure du seuil de perception sensorielle (CPT) chez le volontaire sain. Ce test nécessite l’application d’un courant électrique transcutané qui augmente graduellement et qui, selon la fréquence choisie, est capable de stimuler spécifiquement les fibres nerveuses impliquées dans le cheminement de l’influx nerveux douloureux. Les résultats obtenus chez les volontaires sains indiquent que la mesure CPT est fiable, reproductible et permet de suivre l’évolution temporelle du bloc sensitif. Études cliniques Manuscrit 3 : Nous avons ensuite caractérisé, pendant plus de 72 h, l’absorption systémique de la ROP lorsqu’administrée pour un bloc du nerf fémoral chez 19 patients subissant une chirurgie du genou. Le modèle PK populationnel utilisé pour analyser nos résultats comporte une absorption biphasique durant laquelle une fraction de la dose administrée pénètre rapidement (temps d’absorption moyen : 27 min, IC % 19 – 38 min) dans le flux sanguin systémique pendant que l’autre partie, en provenance du site de dépôt, est redistribuée beaucoup plus lentement (demi-vie (T1/2) : 2.6 h, IC % 1.6 – 4.3 h) vers la circulation systémique. Une relation statistiquement significative entre l’âge de nos patients et la redistribution de l’AL suggère que la perméabilité tissulaire est augmentée avec l’âge. Manuscrit 4 : Une analyse PK-PD du comportement sensitif du bloc fémoral (CPT) a été effectuée. Le modèle développé a estimé à 20.2 ± 10.1 mg la quantité de ROP nécessaire au site d’action pour produire 90 % de l’effet maximal (AE90). À 2 X la AE90, le modèle prédit un début d’action de 23.4 ± 12.5 min et une durée de 22.9 ± 5.3 h. Il s’agit de la première étude ayant caractérisé le comportement sensitif d’un bloc nerveux périphérique. Manuscrit 5 : La troisième et dernière étude clinique a été conduite chez les patients qui devaient subir une chirurgie du genou sous rachianesthésie. Tout comme pour le bloc du nerf fémoral, le modèle PK le plus approprié pour nos données suggère que l’absorption systémique de la ROP à partir du liquide céphalo-rachidien est biphasique; c.à.d. une phase initiale (T1/2 : 49 min, IC %: 24 – 77 min) suivie (délai: 18 ± 2 min) d'une phase légèrement plus lente (T1/2 : 66 min, IC %: 36 – 97 min). L’effet maximal a été observé beaucoup plus rapidement, soit aux environs de 12.6 ± 4.9 min, avant de revenir aux valeurs de base 210 ± 55 min suivant l’administration de l’agent. Ces données ont permis d’estimer une AE50 de 7.3 ± 2.3 mg pour l'administration spinale. Conclusion : En somme, ces modèles peuvent être utilisés pour prédire l’évolution temporelle du bloc sensitif de l’anesthésie rachidienne et périphérique (fémorale), et par conséquent, optimiser l’utilisation clinique de la ROP en fonction des besoins des cliniciens, notamment en ce qui a trait à l’âge du patient.

Decision-making in a phase II clinical trial: a new approach combining Bayesian and frequentist concepts

The aim of a phase H clinical trial is to decide whether or not to develop an experimental therapy further through phase III clinical evaluation. In this paper, we present a Bayesian approach to the phase H trial, although we assume that subsequent phase III clinical trials will hat,e standard frequentist analyses. The decision whether to conduct the phase III trial is based on the posterior predictive probability of a significant result being obtained. This fusion of Bayesian and frequentist techniques accepts the current paradigm for expressing objective evidence of therapeutic value, while optimizing the form of the phase II investigation that leads to it. By using prior information, we can assess whether a phase II study is needed at all, and how much or what sort of evidence is required. The proposed approach is illustrated by the design of a phase II clinical trial of a multi-drug resistance modulator used in combination with standard chemotherapy in the treatment of metastatic breast cancer. Copyright (c) 2005 John Wiley & Sons, Ltd.

Data-driven treatment selection for seamless phase II/III trials incorporating early-outcome data

Seamless phase II/III clinical trials are conducted in two stages with treatment selection at the first stage. In the first stage, patients are randomized to a control or one of k > 1 experimental treatments. At the end of this stage, interim data are analysed, and a decision is made concerning which experimental treatment should continue to the second stage. If the primary endpoint is observable only after some period of follow-up, at the interim analysis data may be available on some early outcome on a larger number of patients than those for whom the primary endpoint is available. These early endpoint data can thus be used for treatment selection. For two previously proposed approaches, the power has been shown to be greater for one or other method depending on the true treatment effects and correlations. We propose a new approach that builds on the previously proposed approaches and uses data available at the interim analysis to estimate these parameters and then, on the basis of these estimates, chooses the treatment selection method with the highest probability of correctly selecting the most effective treatment. This method is shown to perform well compared with the two previously described methods for a wide range of true parameter values. In most cases, the performance of the new method is either similar to or, in some cases, better than either of the two previously proposed methods.

Cediranib Plus FOLFOX/CAPOX Versus Placebo Plus FOLFOX/CAPOX in Patients With Previously Untreated Metastatic Colorectal Cancer: A Randomized, Double-Blind, Phase III Study (HORIZON II)

Purpose Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC). Patients and Methods Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2: 1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points. Results In all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. Conclusion Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC. J Clin Oncol 30:3596-3603. (C) 2012 by American Society of Clinical Oncology

The ARIQUELI study: potentiation of quetiapine in bipolar I nonresponders with lithium versus aripiprazole

Abstract Background:The treatment of bipolar disorder (BD) remains a challenge due to the complexity of the disease. Current guidelines represent an effort to assist clinicians in routine practice but have several limitations, particularly concerning long-term treatment. The ARIQUELI (efficacy and tolerability of the combination of lithium or aripiprazole in young bipolar non or partial responders to quetiapine monotherapy) study aims to evaluate two different augmentation strategies for quetiapine nonresponders or partial responders in acute and maintenance phases of BD treatment. Methods/Design: The ARIQUELI study is a single-site, parallel-group, randomized, outcome assessor-blinded trial. BD I patients according to the DSM-IV-TR, in depressive, manic/hypomanic or mixed episode, aged 18 to 40 years, are eligible. After diagnostic assessments, patients initiated treatment in phase I with quetiapine. Nonresponders or partial responders after 8 weeks are allocated into one of two groups, potentiated with either lithium (0.5 to 0.8 mEq/l) or aripiprazole (10 or 15 mg). Patients will be followed up for 8 weeks in phase I (acute treatment), 6 months in phase II (continuation treatment) and 12 months in phase III (maintenance treatment). Outcome assessors are blinded to the treatment. The primary outcome is the evaluation of changes in mean scores on the CGI-BP-M between baseline and the endpoint at the end of each study phase. Discussion: The ARIQUELI study is currently in progress, with patients undergoing acute treatment (phase I), potentiation (phase II) and maintenance (phase III). The study will be extended until January 2015. Trials comparing lithium and aripiprazole with potentiate treatment in young BD I nonresponders to quetiapine in monotherapy can provide relevant information on the safety of these drugs in clinical practice. Long-term treatment is an issue of great importance and should be evaluated further through more in-depth studies given that BD is a chronic disease. Trial registration: ClinicalTrials.gov identifier: NCT01710163

Pre-clinical and clinical development of leukemia stem cell inhibitors in acute leukemias

In Leukemias, recent developments have demonstrated that the Hedgehog pathway plays a key-role in the peculiar ability of self renewal of leukemia stem cells. The aim of this research activity was to investigate, through a first in man, Phase I, open label, clinical trial, the role and the impact, mainly in terms of safety profile, adverse events and pharmacokinetics, of a Sonic Hedgehog inhibitor compound on a population of heavely pretreated patients affected by AML, CML, MF, or MDS, resistant or refractory to standard chemotherapy. Thirty-five patients have been enrolled. The drug was administered orally, in 28 days cycles, without rest periods. The compound showed a good safety profile. The half life was of 17-35 hours, justifying the daily administration. Significant signs of activity, in terms of reduction of bone marrow blast cell amount were seen in most of the patients enrolled. Interestingly, correlative biological studies demonstrated that, comparing the gene expression profyiling signature of separated CD34+ cells before and after one cycle of treatment, the most variably expressed genes were involved in the Hh pathway. Moreover, we observed that many genes involved in MDR (multidrug resistance)were significantly down regulated after treatment. These data might lead to future clinical trials based on combinatory approaches, including, for instance, Hh inhibitors and conventional chemotherapy.

Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03)

Patients with brain metastases (BM) rarely survive longer than 6months and are commonly excluded from clinical trials. We explored two combined modality regimens with novel agents with single agent activity and radiosensitizing properties.

A phase IIa randomized controlled pilot study evaluating the safety and clinical outcomes following the use of rhGDF-5/β-TCP in regenerative periodontal therapy

To present the safety profile, the early healing phase and the clinical outcomes at 24 weeks following treatment of human intrabony defects with open flap debridement (OFD) alone or with OFD and rhGDF-5 adsorbed onto a particulate β-tricalcium phosphate (β-TCP) carrier. Twenty chronic periodontitis patients, each with at least one tooth exhibiting a probing depth ≥6 mm and an associated intrabony defect ≥4 mm entered the study. Ten subjects (one defect/patient) were randomized to receive OFD alone (control) and ten subjects OFD combined with rhGDF-5/β-TCP. Blood samples were collected at screening, and at weeks 2 and 24 to evaluate routine hematology and clinical chemistry, rhGDF-5 plasma levels, and antirhGDF-5 antibody formation. Plaque and gingival indices, bleeding on probing, probing depth, clinical attachment level, and radiographs were recorded pre- and 24 weeks postsurgery. Comparable safety profiles were found in the two treatment groups. Neither antirhGDF-5 antibody formation nor relevant rhGDF-5 plasma levels were detected in any patient. At 6 months, treatment with OFD + rhGDF-5/β-TCP resulted in higher but statistically not significant PD reduction (3.7 ± 1.2 vs. 3.1 ± 1.8 mm; p = 0.26) and CAL gain (3.2 ± 1.7 vs. 1.7 ± 2.2 mm; p = 0.14) compared to OFD alone. In the tested concentration, the use of rhGDF-5/β-TCP appeared to be safe and the material possesses a sound biological rationale. Thus, further adequately powered, randomized controlled clinical trials are warranted to confirm the clinical relevance of this new approach in regenerative periodontal therapy. rhGDF-5/β-TCP may represent a promising new techology in regenerative periodontal therapy.

RNA polymerase II large subunit degradation induced by ecteinascidin 743: Molecular characterization and subsequent rational investigation of antitumor mechanisms in cancers with clinical response

Ecteinascidin 743 (Et-743), which is a novel DNA minor groove alkylator with a unique spectrum of antitumor activity, is currently being evaluated in phase II/III clinical trials. Although the precise molecular mechanisms responsible for the observed antitumor activity are poorly understood, recent data suggests that post-translational modifications of RNA polymerase II Large Subunit (RNAPII LS) may play a central role in the cellular response to this promising anticancer agent. The stalling of an actively transcribing RNAPII LS at Et-743-DNA adducts is the initial cellular signal for transcription-coupled nucleotide excision repair (TC-NER). In this manner, Et-743 poisons TC-NER and produces DNA single strand breaks. Et-743 also inhibits the transcription and RNAPII LS-mediated expression of selected genes. Because the poisoning of TC-NER and transcription inhibition are critical components of the molecular response to Et-743 treatment, we have investigated if changes in RNAPII LS contribute to the disruption of these two cellular pathways. In addition, we have studied changes in RNAPII LS in two tumors for which clinical responses were reported in phase I/II clinical trials: renal cell carcinoma and Ewing's sarcoma. Our results demonstrate that Et-743 induces degradation of the RNAPII LS that is dependent on active transcription, a functional 26S proteasome, and requires functional TC-NER, but not global genome repair. Additionally, we have provided the first experimental data indicating that degradation of RNAPII LS might lead to the inhibition of activated gene transcription. A set of studies performed in isogenic renal carcinoma cells deficient in von Hippel-Lindau protein, which is a ubiquitin-E3-ligase for RNAPII LS, confirmed the central role of RNAPII LS degradation in the sensitivity to Et-743. Finally, we have shown that RNAPII LS is also degraded in Ewing's sarcoma tumors following Et-743 treatment and provide data to suggest that this event plays a role in decreased expression of the Ewing's sarcoma oncoprotein, EWS-Fli1. Altogether, these data implicate degradation of RNAPII LS as a critical event following Et-743 exposure and suggest that the clinical activity observed in renal carcinoma and Ewing's sarcoma may be mediated by disruption of molecular pathways requiring a fully functional RNAPII LS. ^

Does immediate loading affect clinical and patient-centered outcomes of mandibular 2-unsplinted-implant overdenture? : a 2-year within-case analysis

Objective To provide 2-year clinical- and patient-oriented data with regard to mandibular overdenture assisted by 2 immediately loaded unsplinted implants. Material and methods In this pre-post design, Phase-I clinical trial, 18 edentate individuals (62.4 ± 7.7 years) received a new set of complete denture. Then, following standard procedures, 3 threaded implants (OsseoSpeed TX™, Dentsply Implants, Mölndal, Sweden) were placed in the mandible in each patient, and locator abutments (Zest Anchors LLC, Escondido, U.S.A.) were inserted on the right and left side implants. The midline implant served as a control for within-patient comparison. The immediate loading was conducted within 24 h of surgery. Data were collected at baseline (T0), 12 (T1) and 24 (T2) months after immediate loading. The clinical outcomes included implant survival rate, crestal bone level changes and implant stability. These criteria were assessed through clinical and radiographic examinations as well as resonance frequency analysis. Patient-centered outcomes included patient satisfaction and oral health-related quality of life measured using validated questionnaires. Brunner-Langer approach was used for statistical analysis. Results Implant survival rate for immediate loaded implants was 91.7% at 2-year follow-up. None of the unloaded implants failed. There was no statistically significant difference at baseline and follow-ups with regard to clinical outcomes between loaded and unloaded implants. Patient satisfaction and quality of life improved (p < 0.0001) from baseline to 2-year follow-up. Conclusion Immediate loading protocol did not negatively affect clinical outcomes, satisfaction and quality of life of patients wearing 2-unsplinted-implant mandibular overdenture for 2 years. This conclusion requires confirmation by randomized control trials. Clinical significance statement Mandibular overdenture assisted by two immediately-loaded unsplinted implants is successful treatment based on 2-year clinical and patient-based outcomes.

Does immediate loading affect clinical and patient-centered outcomes of mandibular 2-unsplinted-implant overdenture? : a 2-year within-case analysis

Objective To provide 2-year clinical- and patient-oriented data with regard to mandibular overdenture assisted by 2 immediately loaded unsplinted implants. Material and methods In this pre-post design, Phase-I clinical trial, 18 edentate individuals (62.4 ± 7.7 years) received a new set of complete denture. Then, following standard procedures, 3 threaded implants (OsseoSpeed TX™, Dentsply Implants, Mölndal, Sweden) were placed in the mandible in each patient, and locator abutments (Zest Anchors LLC, Escondido, U.S.A.) were inserted on the right and left side implants. The midline implant served as a control for within-patient comparison. The immediate loading was conducted within 24 h of surgery. Data were collected at baseline (T0), 12 (T1) and 24 (T2) months after immediate loading. The clinical outcomes included implant survival rate, crestal bone level changes and implant stability. These criteria were assessed through clinical and radiographic examinations as well as resonance frequency analysis. Patient-centered outcomes included patient satisfaction and oral health-related quality of life measured using validated questionnaires. Brunner-Langer approach was used for statistical analysis. Results Implant survival rate for immediate loaded implants was 91.7% at 2-year follow-up. None of the unloaded implants failed. There was no statistically significant difference at baseline and follow-ups with regard to clinical outcomes between loaded and unloaded implants. Patient satisfaction and quality of life improved (p < 0.0001) from baseline to 2-year follow-up. Conclusion Immediate loading protocol did not negatively affect clinical outcomes, satisfaction and quality of life of patients wearing 2-unsplinted-implant mandibular overdenture for 2 years. This conclusion requires confirmation by randomized control trials. Clinical significance statement Mandibular overdenture assisted by two immediately-loaded unsplinted implants is successful treatment based on 2-year clinical and patient-based outcomes.

Clinical response after intradermal immature dendritic cell vaccination in metastatic melanoma is associated with immune response to particulate antigen

Metastatic melanoma is poorly responsive to treatment, and immunotherapeutic approaches are potentially beneficial. Predictors of clinical response are needed to identify suitable patients. We sought factors associated with melanoma-specific clinical response following intradermal vaccination with autologous melanoma peptide and particulate hepatitis B antigen (HBsAg)-exposed immature monocyte-derived dendritic cells (MDDC). Nineteen patients with metastatic melanoma received a maximum of 8, 2-weekly vaccinations of DC, exposed to HBsAg in addition to autologous melanoma peptides. A further 3 patients received an otherwise identical vaccine that did not include HBsAg. Patients were assessed 1-2 monthly for safety, disease volume, and cellular responses to HBsAg and melanoma peptide. There was no significant toxicity. Of 19 patients receiving HBsAg-exposed DC, 9 primed or boosted a cellular response to HBsAg, and 10 showed no HBsAg response. HBsAg-specific responses were associated with in vitro T cell responses to melanoma peptides and to phytohemagglutinin (PHA). Zero out of 10 non-HBsAg-responding and 4/9 HBsAg-responding patients achieved objective melanoma-specific clinical responses or disease stabilization- 1 complete and 2 partial responses and I case of stable disease (P=0.018). Development of melanoma-specific cellular immunity and T cell responsiveness to mitogen were greater in the group of patients responding to HBsAg. Therefore stimulation of an immune response to nominal particulate antigen was necessary when presented by melanoma peptide-exposed immature DC, to achieve clinical responses in metastatic melanoma. Since general immune competence may be a determinant of treatment response, it should be assessed in future trials on DC immunotherapy.

Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-I trials

Objectives: To investigate the effectiveness of valerian for the management of chronic insomnia in general practice. Design: Valerian versus placebo in a series of n-of-1 trials, in Queensland, Australia. Results: Of 42 enrolled patients, 24 (57%) had sufficient data for inclusion into the n-of-1 analysis. Response to valerian was fair for 23 (96%) participants evaluating their 'energy level in the previous day' but poor or modest for all 24 (100%) participants' response to 'total sleep time' and for 23 (96%) participants' response to 'number of night awakenings' and 'morning refreshment'. As a group, the proportion of treatment successes ranged from 0.35 (95% CI 0.23, 0.47) to 0.55 (95% CI 0.43, 0.67) for the six elicited outcome sleep variables. There was no significant difference in the number (P = 0.06), distribution (P = 1.00) or severity (P = 0.46) of side effects between valerian and placebo treatments. Conclusions: Valerian was not shown to be appreciably better than placebo in promoting sleep or sleep-related factors for any individual patient or for all patients as a group. (C) 2003 Elsevier Ltd. All rights reserved.

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (Chimeri Vax -DEN2) Vaccine: Phase 1 clinical trial for safety and immunogenicity

A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax™-DEN2) in comparison to that of YF vaccine (YF-VAX®). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax™-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAXâ by the subcutaneous route (SC). To determine the effect of YF pre-immunity on the ChimeriVaxTM-DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax™-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX® and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log10 PFU of ChimeriVaxTM-DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX® seroconverted to YF 17D virus but none of YF naïve subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3, and 4 were observed in YF naïve subjects inoculated with either ChimeriVax™-DEN2 or YF-VAX®. In contrast, 100% of YF immune subjects inoculated with ChimeriVax™-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2, and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that 1) the safety and immunogenicity profile of the ChimeriVax™-DEN2 vaccine is consistent with that of YF-VAX®, and 2) pre-immunity to YF virus does not interfere with ChimeriVaxTM-DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.