An illustration of the modelling of cost and efficacy data from a clinical trial

Health care providers, purchasers and policy makers need to make informed decisions regarding the provision of cost-effective care. When a new health care intervention is to be compared with the current standard, an economic evaluation alongside an evaluation of health benefits provides useful information for the decision making process. We consider the information on cost-effectiveness which arises from an individual clinical trial comparing the two interventions. Recent methods for conducting a cost-effectiveness analysis for a clinical trial have focused on the net benefit parameter. The net benefit parameter, a function of costs and health benefits, is positive if the new intervention is cost-effective compared with the standard. In this paper we describe frequentist and Bayesian approaches to cost-effectiveness analysis which have been suggested in the literature and apply them to data from a clinical trial comparing laparoscopic surgery with open mesh surgery for the repair of inguinal hernias. We extend the Bayesian model to allow the total cost to be divided into a number of different components. The advantages and disadvantages of the different approaches are discussed. In January 2001, NICE issued guidance on the type of surgery to be used for inguinal hernia repair. We discuss our example in the light of this information. Copyright © 2003 John Wiley & Sons, Ltd.

Using historical lesion volume data in the design of a new phase II clinical trial in acute stroke

Background and Purpose-Clinical research into the treatment of acute stroke is complicated, is costly, and has often been unsuccessful. Developments in imaging technology based on computed tomography and magnetic resonance imaging scans offer opportunities for screening experimental therapies during phase II testing so as to deliver only the most promising interventions to phase III. We discuss the design and the appropriate sample size for phase II studies in stroke based on lesion volume. Methods-Determination of the relation between analyses of lesion volumes and of neurologic outcomes is illustrated using data from placebo trial patients from the Virtual International Stroke Trials Archive. The size of an effect on lesion volume that would lead to a clinically relevant treatment effect in terms of a measure, such as modified Rankin score (mRS), is found. The sample size to detect that magnitude of effect on lesion volume is then calculated. Simulation is used to evaluate different criteria for proceeding from phase II to phase III. Results-The odds ratios for mRS correspond roughly to the square root of odds ratios for lesion volume, implying that for equivalent power specifications, sample sizes based on lesion volumes should be about one fourth of those based on mRS. Relaxation of power requirements, appropriate for phase II, lead to further sample size reductions. For example, a phase III trial comparing a novel treatment with placebo with a total sample size of 1518 patients might be motivated from a phase II trial of 126 patients comparing the same 2 treatment arms. Discussion-Definitive phase III trials in stroke should aim to demonstrate significant effects of treatment on clinical outcomes. However, more direct outcomes such as lesion volume can be useful in phase II for determining whether such phase III trials should be undertaken in the first place. (Stroke. 2009;40:1347-1352.)

A Bayesian approach for dose-escalation in a phase I clinical trial incorporating pharmacodynamic endpoints

Bayesian decision procedures have already been proposed for and implemented in Phase I dose-escalation studies in healthy volunteers. The procedures have been based on pharmacokinetic responses reflecting the concentration of the drug in blood plasma and are conducted to learn about the dose-response relationship while avoiding excessive concentrations. However, in many dose-escalation studies, pharmacodynamic endpoints such as heart rate or blood pressure are observed, and it is these that should be used to control dose-escalation. These endpoints introduce additional complexity into the modeling of the problem relative to pharmacokinetic responses. Firstly, there are responses available following placebo administrations. Secondly, the pharmacodynamic responses are related directly to measurable plasma concentrations, which in turn are related to dose. Motivated by experience of data from a real study conducted in a conventional manner, this paper presents and evaluates a Bayesian procedure devised for the simultaneous monitoring of pharmacodynamic and pharmacokinetic responses. Account is also taken of the incidence of adverse events. Following logarithmic transformations, a linear model is used to relate dose to the pharmacokinetic endpoint and a quadratic model to relate the latter to the pharmacodynamic endpoint. A logistic model is used to relate the pharmacokinetic endpoint to the risk of an adverse event.

Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome

Gut microflora-mucosal interactions may be involved in the pathogenesis of irritable bowel syndrome (IBS). To investigate the efficacy of a novel prebiotic trans-galactooligosaccharide in changing the colonic microflora and improve the symptoms in IBS sufferers. In all, 44 patients with Rome II positive IBS completed a 12-week single centre parallel crossover controlled clinical trial. Patients were randomized to receive either 3.5 g/d prebiotic, 7 g/d prebiotic or 7 g/d placebo. IBS symptoms were monitored weekly and scored according to a 7-point Likert scale. Changes in faecal microflora, stool frequency and form (Bristol stool scale) subjective global assessment (SGA), anxiety and depression and QOL scores were also monitored. The prebiotic significantly enhanced faecal bifidobacteria (3.5 g/d P < 0.005; 7 g/d P < 0.001). Placebo was without effect on the clinical parameters monitored, while the prebiotic at 3.5 g/d significantly changed stool consistency (P < 0.05), improved flatulence (P < 0.05) bloating (P < 0.05), composite score of symptoms (P < 0.05) and SGA (P < 0.05). The prebiotic at 7 g/d significantly improved SGA (P < 0.05) and anxiety scores (P < 0.05). The galactooligosaccharide acted as a prebiotic in specifically stimulating gut bifidobacteria in IBS patients and is effective in alleviating symptoms. These findings suggest that the prebiotic has potential as a therapeutic agent in IBS.

A randomised clinical trial to assess the effect of total enteral and total parenteral nutritional support on metabolic, inflammatory and oxidative markers in patients with predicted severe acute pancreatitis (APACHE II >= 66)

Background: Total enteral nutrition (TEN) within 48 h of admission has recently been shown to be safe and efficacious as part of the management of severe acute pancreatitis. Our aim was to ascertain the safety of immediate TEN in these patients and the effect of TEN on systemic inflammation, psychological state, oxidative stress, plasma glutamine levels and endotoxaemia. Methods: Patients admitted with predicted severe acute pancreatitis (APACHE II score 15) were randomised to total enteral (TEN; n = 8) or total parenteral nutrition (TPN; n = 9). Measurements of systemic inflammation (C-reactive protein), fatigue ( visual analogue scale), oxidative stress ( plasma thiobarbituric acid- reactive substances), plasma glutamine and anti-endotoxin IgG and IgM antibody concentrations were made on admission and repeated on days 3 and 7 thereafter. Clinical progress was monitored using APACHE II score. Organ failure and complications were recorded. Results: All patients tolerated the feeding regime well with few nutrition-related complications. Fatigue improved in both groups but more rapidly in the TEN group. Oxidative stress was high on admission and rose by similar amounts in both groups. Plasma glutamine concentrations did not change significantly in either group. In the TPN group, 3 patients developed respiratory failure and 3 developed non-respiratory single organ failure. There were no such complications in the TEN group. Hospital stay was shorter in the TEN group [ 7 (4-14) vs. 10 (7-26) days; p = 0.05] as was time to passing flatus and time to opening bowels [1 (0-2) vs. 2 (1-5) days; p = 0.01]. The cost of TEN was considerably less than of TPN. Conclusion: Immediate institution of nutritional support in the form of TEN is safe in predicted severe acute pancreatitis. It is as safe and as efficacious as TPN and may be beneficial in the clinical course of this disease. Copyright (C) 2003 S. Karger AG, Basel and IAP.

Adding a treatment arm to an ongoing clinical trial: a review of methodology and practice

Incorporating an emerging therapy as a new randomisation arm in a clinical trial that is open to recruitment would be desirable to researchers, regulators and patients to ensure that the trial remains current, new treatments are evaluated as quickly as possible, and the time and cost for determining optimal therapies is minimised. It may take many years to run a clinical trial from concept to reporting within a rapidly changing drug development environment; hence, in order for trials to be most useful to inform policy and practice, it is advantageous for them to be able to adapt to emerging therapeutic developments. This paper reports a comprehensive literature review on methodologies for, and practical examples of, amending an ongoing clinical trial by adding a new treatment arm. Relevant methodological literature describing statistical considerations required when making this specific type of amendment is identified, and the key statistical concepts when planning the addition of a new treatment arm are extracted, assessed and summarised. For completeness, this includes an assessment of statistical recommendations within general adaptive design guidance documents. Examples of confirmatory ongoing trials designed within the frequentist framework that have added an arm in practice are reported; and the details of the amendment are reviewed. An assessment is made as to how well the relevant statistical considerations were addressed in practice, and the related implications. The literature review confirmed that there is currently no clear methodological guidance on this topic, but that guidance would be advantageous to help this efficient design amendment to be used more frequently and appropriately in practice. Eight confirmatory trials were identified to have added a treatment arm, suggesting that trials can benefit from this amendment and that it can be practically feasible; however, the trials were not always able to address the key statistical considerations, often leading to uninterpretable or invalid outcomes. If the statistical concepts identified within this review are considered and addressed during the design of a trial amendment, it is possible to effectively assess a new treatment arm within an ongoing trial without compromising the original trial outcomes.

Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial

Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Impact of a nutritional counseling program on prevention of HAART-related metabolic and morphologic abnormalities

The advent of highly active antiretroviral therapy (HAART) improved HIV infection prognosis. However, adverse metabolic and morphologic effects emerged, highlighting a lack of investigation into the role of nutritional interventions among this population. The present study evaluated the impact of a nutritional counseling program on prevention of morphologic and metabolic changes in patients living with HIV/AIDS receiving HAART. A 12-month randomized clinical trial was conducted with 53 adults of both genders in use of HAART. Subjects were allocated to either an intervention group (IG) or a control group (CG). Nutritional counseling was based on the promotion of a healthy diet pattern. Anthropometrical, biochemical, blood pressure, and food intake variables were assessed on four separate occasions. Sub scapular skin-fold results showed a significant tendency for increase between time 1 (Mean IG = 14.9 mm; CG = 13.6 mm), time 3 (Mean IG = 16.7 mm; CG = 18.2 mm), and time 4 (Mean IG = 16.4 mm; CG = 17.7 mm). Lipid percentage intake presented a greater increase among controls (time 1 mean = 26.3%, time 4 mean = 29.6%) than among IG subjects (time 1 mean = 29.1%, time 4 mean = 28.9%). Moreover, participants allocated to the IG presented an increase in dietetic fiber intake of almost 10 grams. The proposed nutritional counseling program proved to be effective in improving diet by reducing fat consumption and increasing fiber intake.

Prospective Clinical Trial Comparing Outcome Measures Between Furlow and von Langenbeck Palatoplasties for UCLP

The goal of this prospective randomized clinical trial was to compare 2 cohorts of standardized cleft patients with regard to functional speech outcome and the presence or absence of palatal fistulae. The 2 cohorts are randomized to undergo either a conventional von Langenbeck repair with intravelar velarplasty or the double-opposing Z-plasty Furlow procedure. A prospective 2 x 2 x 2 factorial clinical trial was used in which each subject was randomly assigned to 1 of 8 different groups: 1 of 2 different lip repairs (Spina vs. Millard), 1 of 2 different palatal repair (von Langenbeck vs. Furlow), and 1 of 2 different ages at time of palatal surgery (9-12 months vs. 15-18 months). All surgeries were performed by the same 4 surgeons. A cul-de-sac test of hypernasality and a mirror test of nasal air emission were selected as primary outcome measures for velopharyngeal function. Both a surgeon and speech pathologist examined patients for the presence of palatal fistulae. In this study, the Furlow double-opposing Z-palatoplasty resulted in significantly better velopharyngeal function for speech than the von Langenbeck procedure as determined by the perceptual cul-de-sac test of hypernasality. Fistula occurrence was significantly higher for the Furlow procedure than for the von Langenbeck. Fistulas were more likely to occur in patients with wider clefts and when relaxing incisions were not used.

Intravitreal injection versus sub-Tenon's infusion of triamcinolone acetonide for refractory diabetic macular edema: A randomized clinical trial

PURPOSE. To compare the effectiveness of posterior sub-Tenon's infusion (STi) and intravitreal injection (IVI) of triamcinolone acetonide (TA) for treatment of refractory diffuse diabetic macular edema.METHODS. Thirty-six phakic diabetic patients with refractory diffuse diabetic macular edema were prospectively enrolled. Patients randomly received either 40 mg STi or 4 mg IVI of TA. Comprehensive ophthalmic evaluation was performed at baseline and 1, 2, 4, 8 +/- 1, 12 +/- 2 and 24 +/- 2 weeks after treatment. Macular morphologic changes detected by optical coherence tomography and visual acuity, intraocular pressure, and lens status were evaluated.RESULTS. Twenty-eight patients (28 eyes) completed the 24-week study. Central macular thickness was significantly reduced in the IVI group when compared with the STi group at 2, 4, 8, 12, and 24 weeks after treatment (P < 0.01). Mean visual acuities (in logarithm of the minimum angle of resolution [logMAR]) at week-4, -8, and -12 follow-up examinations were significantly higher in the IVI group (0.74, 0.75, and 0.82, respectively) when compared with the STi group (0.88, 0.88, and 0.90, respectively; P < 0.01). A significant change from baseline in mean intraocular pressure (mm Hg) was seen at weeks 4 (+/- 3.21) and 8 (+/- 3.35) in STi the group (P < 0.01), and at week 8 (+/- 2.78) in the IVI group (P < 0.05). No patient had cataract progression during the study.CONCLUSIONS. Although the number of patients and length of follow-up in this preliminary study were limited, the changes in central macular thickness and visual acuity observed after treatment suggest that IVI TA may be more effective than STi for the management of refractory diffuse diabetic macular edema. Further studies are needed to confirm these preliminary findings.

Effectiveness and safety of endotracheal tube cuffs filled with air versus filled with alkalinized lidocaine: a randomized clinical trial

CONTEXTO E OBJETIVO: Os tubos traqueais são dispositivos utilizados para manutenção da ventilação. A hiperinsuflação do balonete do tubo traqueal, causada pela difusão do óxido nitroso (N2O), pode determinar lesões traqueais, que se manifestam clinicamente como odinofagia, rouquidão e tosse. A lidocaína, quando injetada no balonete do tubo traqueal, difunde-se através de sua parede, determinando ação anestésica local na traquéia. O objetivo foi avaliar a efetividade e a segurança do balonete do tubo traqueal preenchido com ar comparado com o balonete preenchido com lidocaína, considerando os desfechos: sintomas cardiovasculatórios (HAS, taquicardia); odinofagia, tosse, rouquidão e tolerância ao tubo traqueal. TIPO DE ESTUDO E LOCAL: Estudo clínico prospectivo, realizado no Departamento de Anestesiologia da Faculdade de Medicina da Unesp, campus de Botucatu. MÉTODOS: A pressão do balonete do tubo traqueal foi medida, entre 50 pacientes, antes, 30, 60, 90 e 120 minutos após o início da inalação de N2O anestésico. As pacientes foram distribuídas aleatoriamente em dois grupos: Air, em que o balonete foi inflado com ar para obtenção de pressão de 20 cm H2O, e Lido, em que o balonete foi preenchido com lidocaína a 2% mais bicarbonato de sódio a 8,4% para obtenção da mesma pressão. O desconforto antes da extubação, e manifestações clínicas como dor de garganta, rouquidão e tosse foram registrados no momento da alta da unidade de cuidados pós-anestésicos, e dor de garganta e rouquidão foram avaliadas também 24 horas após a anestesia. RESULTADOS: Os valores da pressão no balonete em G2 foram significativamente menores do que os de Air em todos os tempos de estudo, a partir de 30 minutos (p < 0,001). A proporção de pacientes que reagiu ao tubo traqueal no momento da desintubação foi significantemente menor em Lido (p < 0,005). A incidência de odinofagia foi significantemente menor em Lido no primeiro dia de pós-operatório (p < 0,05). A incidência de tosse e rouquidão não diferiu entre os grupos. CONCLUSÕES: Durante ventilação artificial, empregando-se a mistura de oxigênio e N2O, a insuflação do balonete com lidocaína 2% alcalinizada impede que ocorra aumento significante da pressão no balonete e determina maior tolerância ao tubo traqueal e menor incidência de odinofagia no pós-operatório, podendo então ser considerada mais segura e com maior efetividade.

Labor analgesia with ropivacaine added to clonidine: a randomized clinical trial

CONTEXTO E OBJETIVO: A associação entre ropivacaína e clonidina agiria menos que a ropivacaína isolada na mãe e no feto? Foram pesquisados os efeitos materno-fetais de duas técnicas farmacológicas: pequena dose de ropivacaína ou dose menor de ropivacaína mais clonidina na analgesia peridural para parto. TIPO DE ESTUDO E LOCAL: Estudo prospectivo, Departamento de Anestesiologia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista. MÉTODOS: Trinta e duas parturientes, estado físico de acordo com a American Society of Anesthesiologists I e II, foram aleatoriamente submetidas à analgesia peridural com 15 ml de ropivacaína 0,125% (grupo R) ou 15 ml de ropivacaína 0,0625% mais clonidina, 75 µg (grupo RC). Foram avaliados: intensidade da dor, nível do bloqueio sensitivo, latência, intensidade do bloqueio motor, duração da analgesia de parto e da analgesia peridural. Os neonatos foram avaliados pelo Apgar e método de Amiel-Tison (capacidade neurológica e adaptativa). RESULTADOS: Não houve diferenças significativas entre grupos para dor, nível de bloqueio sensitivo, duração da analgesia peridural e Apgar. Para latência, duração da analgesia de parto e bloqueio motor, grupo R < grupo RC. O escore da capacidade neurológica e adaptativa de meia e duas horas foi maior para o grupo R. Cem por cento dos neonatos do grupo R e 75% dos do grupo RC estavam neurologicamente saudáveis ao exame de 24 horas. CONCLUSÃO: Pequena dose de ropivacaína e dose menor mais clonidina aliviaram a dor materna durante o parto. Neonatos de mães que receberam apenas ropivacaína mostraram melhores escores da capacidade neurológica e adaptativa.