A phase 2, double-blind, placebo-controlled trial of a valproate/lithium combination in ALS patients.

BACKGROUND: Few treatments are currently available for amyotrophic lateral sclerosis (ALS). A combination of lithium carbonate and valproic acid (VPA-Li) was shown to inhibit motor neuron death and delay disease progression. METHODS: Outpatients with a typical ALS presentation were enrolled in a randomized, placebo-controlled trial to assess the efficacy of orally administered VPA-Li. Changes in a functional scale score (ALSFRS-R) and survival rate were chosen as primary outcome variables. Secondary outcome variables included BMI, respiratory monitoring, quality of life, and a global impression of the treatment. RESULTS: Out of 42 patients enrolled, 20 individuals receiving VPA-Li and 18 on placebo treatment were included in the final analysis. Forty-five percent of patients receiving VPA-Li completed the trial, whereas only 22.22% of patients in the placebo group attended the final visit 18 months later (P = 0.09). Major changes in the ALSFRS-R score were observed, including a decrease of 1.195 points/month in the placebo group (95% CI: 0.7869-1.6031) and of 0.5085 under VPA-Li treatment (95% CI: 0.2288-0.7882) between months 6 and 14. Adverse events included bad mouth taste, constipation, and anorexia. Survival rate, body weight, and quality of life were positive outcomes by the end of the trial despite a high sample reduction, especially in the placebo group. The inclusion of 212 subjects in each group would confirm these differences. CONCLUSIONS: Combined VPA-Li treatment associated with slower ALS progression and better secondary outcomes. This dual treatment overcame the futility threshold and merits further investigation in ALS.

Cápsulas de estrógenos más progesterona ayudan a los SVM. Estudio REPLENISH / Estrogen plus progesterone capsules help the SVM. REPLENISH study

El estudio REPLENISH, un ensayo multicéntrico aleatorizado, doble ciego, controlado con placebo de fase 3, de 12 meses, evaluó la eficacia, la seguridad endometrial y la seguridad general de una sola cápsula de 17-estradiol más progesterona (E + P) para el tratamiento moderado a síntomas vasomotores severos (SVM).

The REPLENISH study, a 12-month, multicenter, randomized, double-blind, phase 3 placebo-controlled trial, evaluated the efficacy, endometrial safety and overall safety of a single 17-estradiol plus progesterone (E + P) capsule for moderate treatment to severe vasomotor symptoms (SVM).

¿Cuándo lo imparcial se convierte en sesgo? El dilema de las patogenesias homeopáticas y los modernos métodos de investigación / When does the impartial become bias? The dilemma of homeopathic pathogenesis and modern research methods

Desde los años sesenta, los homeópatas, junto con los físicos biomédicos, generalmente han reconocido al ensayo de control doble ciego aleatorio (ECA) como el "estándar de oro" para establecer la eficacia en una intervención clínica. Sin embargo, la profesión homeopática se ha mostrado ambivalente respecto a la incorporación del modelo ECA para la validación interna de los medicamentos homeopáticos. Este texto muestra importantes elementos del ECA, como la evaluación ciega, la aleatoriedad y la inferencia estadística, examinando algunos de los elementos históricos y científicos acerca de su inclusión en las experimentaciones homeopáticas.

[Epidural anaesthesia: Simulated intravascular test dose with S(+) ketamine, lidocaine and adrenaline. A prospective, randomized, double blind and placebo controlled study]. / Anestesia epidural: dosis test intravascular simulada con S(+)-ketamina, lidocaína y adrenalina. Estudio prospectivo, aleatorizado, doble ciego, controlado con placebo.

OBJECTIVE: The use of a test dose in epidural anaesthesia is a safety recommendation. However specificity and sensitivity of the drugs used with this indication have been not conclusive. The main objective of this study was to compare the effectiveness and the adverse effects of a simulated intravascular test dose of adrenaline, lidocaine and S(+)-ketamine. MATERIAL AND METHODS: A prospective, randomized, double blinded, placebo controlled study was designed. ASA I patients scheduled for elective surgery were included. These were randomized to the following study groups: S(+)-ketamine 0.5 mg.kg-1 (S+K group), 5% lidocaine 1.5 mg.kg-1 (L5% group), adrenaline 15µg (ADR group), and physiological saline 3 ml (SF group; control group). An evaluation was made during the first 15 minutes after the study drug was administered. Variables including heart rate (HR) systolic and diastolic blood pressure (sBP and dBP), mean arterial pressure (MAP), and SpO2 were recorded at 0 min (baseline) and at 2, 5, 8, 10 and 15 minutes after drug injection. An increase of at least 20 beats per minute (bpm) in relation to the baseline measurement was considered a positive result, as was an increase sBP >15 mmHg. The clinical effects described as related to iv injection of the study drugs recorded were: sedation-hypnosis, dizziness, nystagmus, metallic taste perception, perioral or facial paresthesias, tinnitus, as well as any other effect the patients mentioned. Sensitivity and specificity were calculated as was the percent increase in the parameters in order to see if these were clinically useful. RESULTS: A total of 80 patients, 20 per group, were included. The sBP, dBP, and MAP were significantly raised at the 2, 5, 8 and 10 minutes measurements in the S(+)K group compared to the rest of the groups (P<.05), as well as HR in the 2, 5, 8, 10 and 15 minute measurements in the S(+)K compared to the rest of the groups (P<.05). Sensitivity and specificity were high, and significant in the S(+)K group from minute 2 to minute 8 compared with the placebo group, as well as percentage points differences in the same interval. There were significant differences in the incidence of sedation-hypnosis, nystagmus and dizziness, which were more frequent in the S(+)K group. There were no differences in the incidence of metallic taste, perioral and facial paresthesias or tinnitus. The effects in the S(+)K group always occurred before minute 5 after drug injection. CONCLUSION: Both lidocaine an adrenaline at the scheduled doses showed low sensitivity and specificity as a simulated iv epidural test dose. S(+)-ketamine could be a feasible marker after accidental iv injection during epidural anaesthesia or analgesia.

ALERGIA A LA PROTEíNA DE LA LECHE DE VACA. EVALUACIóN DE SU RESOLUCIóN ESPONTáNEA POR MEDIO DE DESAFíOS DOBLE CIEGO PLACEBO CONTROLADOS / cows milk allergy. an assesment of its spontaneous resolution through double blind placebo controlled challenges.

Introducción. la alergia a la leche de vaca (aplv) es un problema sanitario global. Su diagnóstico adecuado y su seguimiento son esenciales ya que la leche de vaca es un alimento importante en la dieta de muchos lactantes. los desafíos orales doble ciego controlados por placebo (ddcpc) son la herramienta ideal para el diagnóstico y seguimiento de las alergias alimentarias. este estudio describe las características evolutivas de pacientes con aplv y las posibles variables que la pudieran modificar. material y métodos. Se estudiaron pacientes con diagnóstico de aplv previo con desafíos abiertos. Se catalogaron las reacciones de acuerdo a la normativa dracma. positivas fueron las pruebas en las que se presentaron alteraciones clínicas o variaciones hemodinámicas. negativas fueron aquellas en las que el paciente toleró la leche. Se consideraron edades de inicio y de realización del ddcpc, sexo y patología de aplv. resultados. Se estudiaron 106 pacientes (50 masculinos, 56 femeninos), promedio edad de inicio de síntomas 5,31 m (rango: 1-48 meses) y al procedimiento 23,14 m (5 meses - 5 años), y 13 pruebas positivas. un conjunto se refirió al mecanismo fisiopatológico y se dividió en ige mediadas (n=55) con 8 pruebas positivas y mixtas/celulares (n=51) con 5 pruebas positivas. otro conjunto fueron no gastrointestinales (n=61) con 7 pruebas positivas y gastrointestinales (n=45) con 6 pruebas positivas. todos los grupos fueron similares en cuanto a las variables demográficas. el sexo masculino y el diagnóstico de anafilaxia fueron factores de riesgo para no resolver su aplv (p=0,0125 y p=0,002 respectivamente). conclusiones. el momento de resolución de la aplv es independiente del mecanismo fisiopatológico subyacente o la edad de inicio de los síntomas. en general resuelven el problema de manera espontánea hacia los dos años de vida en más de un 87% de los casos. el sexo masculino (en ige mediadas) y el antecedente de anafilaxia podrían ser factores de riesgo para tener menos probabilidades de resolver la APLV. (AU)

Introduction: cow´s milk allergy (cma) is a global health issue. a proper diagnosis and follow up become essential. double blind placebo controlled challenges (dbpcc) is the gold standard for this purpose. this paper describes clinical evolution and characteristics of cma, as well as variables that may modify the affection course. methods & material: a group of patients, with a previous diagnosis of cma by open challenges, has been studied and its results cataloged according to dracma guidelines. tests with hemodynamic changes or clinical symptoms were considered as positives, while those with no clinical reaction were considered as negatives. variables involved were: age of symptoms starting, age of dbpcc performing, gender and cma clinical manifestations. results: 106 patients has been studied (50 male, 56 female), with a median age of 5,31 mo (range 5 ­ 48 mo) at the starting symptoms, and a median age of 23,14 mo (range 5 mo ­ 5 y) at the performing of dbpcc. 13 tests were negative. as regards to the different immune mechanisms, 55 were ige dependent (8 negative), and 51 were mediated by mixed/cellular (5 negative). patients were divided into two groups: with gastrointestinal symptoms (n=45) and with no gastrointestinal symptoms (n=61). they showed 6 and 7 negative results, respectively. all groups were similar. male gender, and anaphylaxis diagnosis turned out to be risk factors not to resolve cma (p=0,0125 and p=0,002 respectively). conclusions: cma resolution is independent of the immune mechanisms involved or the age of its symptoms starting. cma is solved spontaneously towards the age of two in 87% of the cases. male gender, and anaphylaxis may become risk factors not to resolve cma.(AU)

Diseño a doble ciego y el uso de placebos psicológicos en investigación de resultados en psicoterapia: Es posible? Un estudio piloto de viabilidad / Double blind design and the use of psychological placebos in outcomes research in psychotherapy: Is it possible? A pilot feasibility study

El uso de placebos y diseños a doble ciego ha cumplido un papel crucial en la investigación clínica en Medicina. Su aplicación a la investigación de resultados en psicoterapia ha sido controversial. Muchos autores niegan la posibilidad de su aplicación debido a que el terapeuta debería conocer la condición del procedimiento aplicado. Se presenta detalladamente un estudio en el que se utilizó un procedimiento placebo correspondiente a EMDR (Eye Movement Desensitization and Reprocessing- Desensibilización y Reprocesamiento por Movimientos Oculares) con un Diseño Experimental de Caso Único. Los objetivos fueron los siguientes: poner a prueba la viabilidad de la implementación de un placebo de tipo psicológico en EMDR y la aplicación de un diseño a doble ciego en el estudio de resultados en EMDR. Se seleccionaron tres pacientes que sufrían de Trastorno por Estrés Postraumático. Se estableció una línea de base de la sintomatología presentada. Luego, los sujetos fueron asignados aleatoriamente a tres condiciones experimentales durante tres sesiones: (a) aplicación del protocolo EMDR sin ningún tipo de estimulación con auriculares en silencio (placebo 1), (b) aplicación del protocolo EMDR con estimulación bilateral auditiva simultánea (no alternada) (placebo 2) y (c) aplicación del protocolo estándar de EMDR con estimulación auditiva bilateral alternada (tratamiento activo). Tales procedimientos resultaron igualmente creíbles para el paciente y para el terapeuta. Esto permitió el desarrollo de un diseño de investigación a doble ciego para la investigación de resultados en EMDR. Finalmente, se discuten algunas posibles aplicaciones e implicancias de la introducción del uso de placebos psicológicos y diseño a doble ciego en la investigación en psicoterapia.

Double blind design and placebos have been of crucial importance in medical clinical research. Their use in outcomes research in the field of psychotherapy has been controversial, though. Their feasibility in such case has been denied by many authors based on the assumption that the psychotherapist would need to know the nature of the applied procedure. In view of this, the author has conducted a pilot feasibility study on three subjects within the context of his doctoral dissertation. Said dissertation aims at establishing the role of alternating bilateral auditory stimulation in the processing of traumatic memories as used in the EMDR (Eye Movement Desensitization and Reprocessing) technique. To such end, the EMDR basic principles and procedures are introduced -with particular attention to alternating bilateral auditory stimulation- and a pilot study using placebos during EMDR administration is presented in detail. The goals of this study are testing the feasibility of: (a) using a psychological placebo in EMDR therapy, and (b) applying a double blind design study in EMDR outcomes research. A single case experimental design was performed on three different patients suffering from PTSD (Posttraumatic Stress Disorder). A symptomatology baseline was established through out three weekly sessions using the DTS (Davidson Trauma Scale) and the OQ-45.2 (Outcomes Questionnaire 45.2). First, three CDs were recorded -one with no sound at all (CD-1, silence condition); another one with auditory stimulation consisting of a tic-tac sound recorded in monaural condition, and reproduced simultaneously over both earphones at a rate of one beat per second (CD-2, monaural condition) and a third one with alternating bilateral auditory stimulation consisting of the exact same sound recorded in stereophonic condition, and reproduced alternatively over the left and right earphones (CD-3, stereo condition)-. At a second stage, these three experimental conditions were assigned randomly to the three subjects, who were administered: (a) EMDR protocol without any type of stimulation, with no sound coming out of the earphones using CD-1 (placebo 1), (b) EMDR protocol with simultaneous bilateral auditory stimulation using CD-2 (placebo 2), and (c) EMDR protocol with alternating bilateral auditory stimulation using CD-3 (active treatment). In all cases, the experimental conditions were implemented during three full sessions in which the CDs were reproduced for the subjects through earphones, instead of speakers, to ensure that the psychotherapist was unaware of the actual conditions. Subsequently, the standard EMDR protocol (i.e., with alternating bilateral auditory stimulation) was administered to each subject until the end of the treatment, determined either by the symptoms being resolved or the maximum of ten sessions being completed. As a result of this pilot study, the author concludes that the feasibility of using double blind studies and placebos in EMDR psychotherapy has indeed been established. Since no apparent difficulties in the administration of the placebos were detected during the study, the use of psychological placebos seems viable. Such procedure is equally credible for the patient as well as for the psychotherapist, which renders possible the development of a double blind design in EMDR outcomes research. It should be noted, though, that the credibility of the placebo was not formally assessed, but rather was perceived through the author’s informal observation. Developing assessment criteria and formal tools to evaluate the credibility of placebo procedures is advisable if future investigations on the subject are to be carried. Even though this study was conducted under a Single Case Experimental Design, the placebo procedure employed could be easily adapted for its use in between group’s designs. Finally, some of the possible applications and consequences regarding the introduction of placebos and double blind design in psychotherapy research are discussed.

Diseño a doble ciego y el uso de placebos psicológicos en investigación de resultados en psicoterapia: Es posible? Un estudio piloto de viabilidad / Double blind design and the use of psychological placebos in outcomes research in psychotherapy: Is it possible? A pilot feasibility study

El uso de placebos y diseños a doble ciego ha cumplido un papel crucial en la investigación clínica en Medicina. Su aplicación a la investigación de resultados en psicoterapia ha sido controversial. Muchos autores niegan la posibilidad de su aplicación debido a que el terapeuta debería conocer la condición del procedimiento aplicado. Se presenta detalladamente un estudio en el que se utilizó un procedimiento placebo correspondiente a EMDR (Eye Movement Desensitization and Reprocessing- Desensibilización y Reprocesamiento por Movimientos Oculares) con un Diseño Experimental de Caso Unico. Los objetivos fueron los siguientes: poner a prueba la viabilidad de la implementación de un placebo de tipo psicológico en EMDR y la aplicación de un diseño a doble ciego en el estudio de resultados en EMDR. Se seleccionaron tres pacientes que sufrían de Trastorno por Estrés Postraumático. Se estableció una línea de base de la sintomatología presentada. Luego, los sujetos fueron asignados aleatoriamente a tres condiciones experimentales durante tres sesiones: (a) aplicación del protocolo EMDR sin ningún tipo de estimulación con auriculares en silencio (placebo 1), (b) aplicación del protocolo EMDR con estimulación bilateral auditiva simultánea (no alternada) (placebo 2) y (c) aplicación del protocolo estándar de EMDR con estimulación auditiva bilateral alternada (tratamiento activo). Tales procedimientos resultaron igualmente creíbles para el paciente y para el terapeuta. Esto permitió el desarrollo de un diseño de investigación a doble ciego para la investigación de resultados en EMDR. Finalmente, se discuten algunas posibles aplicaciones e implicancias de la introducción del uso de placebos psicológicos y diseño a doble ciego en la investigación en psicoterapia.(AU)

Double blind design and placebos have been of crucial importance in medical clinical research. Their use in outcomes research in the field of psychotherapy has been controversial, though. Their feasibility in such case has been denied by many authors based on the assumption that the psychotherapist would need to know the nature of the applied procedure. In view of this, the author has conducted a pilot feasibility study on three subjects within the context of his doctoral dissertation. Said dissertation aims at establishing the role of alternating bilateral auditory stimulation in the processing of traumatic memories as used in the EMDR (Eye Movement Desensitization and Reprocessing) technique. To such end, the EMDR basic principles and procedures are introduced -with particular attention to alternating bilateral auditory stimulation- and a pilot study using placebos during EMDR administration is presented in detail. The goals of this study are testing the feasibility of: (a) using a psychological placebo in EMDR therapy, and (b) applying a double blind design study in EMDR outcomes research. A single case experimental design was performed on three different patients suffering from PTSD (Posttraumatic Stress Disorder). A symptomatology baseline was established through out three weekly sessions using the DTS (Davidson Trauma Scale) and the OQ-45.2 (Outcomes Questionnaire 45.2). First, three CDs were recorded -one with no sound at all (CD-1, silence condition); another one with auditory stimulation consisting of a tic-tac sound recorded in monaural condition, and reproduced simultaneously over both earphones at a rate of one beat per second (CD-2, monaural condition) and a third one with alternating bilateral auditory stimulation consisting of the exact same sound recorded in stereophonic condition, and reproduced alternatively over the left and right earphones (CD-3, stereo condition)-. At a second stage, these three experimental conditions were assigned randomly to the three subjects, who were administered: (a) EMDR protocol without any type of stimulation, with no sound coming out of the earphones using CD-1 (placebo 1), (b) EMDR protocol with simultaneous bilateral auditory stimulation using CD-2 (placebo 2), and (c) EMDR protocol with alternating bilateral auditory stimulation using CD-3 (active treatment). In all cases, the experimental conditions were implemented during three full sessions in which the CDs were reproduced for the subjects through earphones, instead of speakers, to ensure that the psychotherapist was unaware of the actual conditions. Subsequently, the standard EMDR protocol (i.e., with alternating bilateral auditory stimulation) was administered to each subject until the end of the treatment, determined either by the symptoms being resolved or the maximum of ten sessions being completed. As a result of this pilot study, the author concludes that the feasibility of using double blind studies and placebos in EMDR psychotherapy has indeed been established. Since no apparent difficulties in the administration of the placebos were detected during the study, the use of psychological placebos seems viable. Such procedure is equally credible for the patient as well as for the psychotherapist, which renders possible the development of a double blind design in EMDR outcomes research. It should be noted, though, that the credibility of the placebo was not formally assessed, but rather was perceived through the author’s informal observation. Developing assessment criteria and formal tools to evaluate the credibility of placebo procedures is advisable if future investigations on the subject are to be carried. Even though this study was conducted under a Single Case Experimental Design, the placebo procedure employed could be easily adapted for its use in between group’s designs. Finally, some of the possible applications and consequences regarding the introduction of placebos and double blind design in psychotherapy research are discussed.(AU)

La revisión por pares y la selección de artículos para publicación / A revisão por pares e a seleção de artigos para publicação / Peer review and selection of articles for publishing

La revisión de manuscritos científicos por pares evaluadores pretende evaluar la originalidad, calidad y pertinencia de datos asociados a una investigación. Con algunas variaciones, este sistema se ha institucionalizado, ha sido parte central en la validación de publicaciones científicas y es aceptado por la mayoría de científicos como la mejor opción de evaluación entre las disponibles. En este artículo se describen brevemente las fortalezas y debilidades de este sistema de evaluación y se reflexiona sobre algunas alternativas para su mejoramiento, lo cual es valioso para revistas de habla española.

Peer review of scientific manuscripts aims to evaluate the originality, quality, and relevance of research data. Although with some variations, this system has been institutionalized, is still a central part in the validation of scientific publications, and is accepted by most scientists as the best evaluation option available. The article briefly describes this evaluation system’s strengths and weaknesses, and reflects on alternatives for its improvement, some of which may prove to be useful for journals published in Spanish.

A revisão de manuscritos científicos por pares avaliadores pretende examinar a originalidade, qualidade e pertinência de dados associados a uma pesquisa. Com algumas variações, este sistema se institucionalizou e é parte central na validação de publicações científicas e é aceito pela maioria dos cientistas como a melhor opção de avaliação entre as disponíveis. Neste artigo, descrevem-se brevemente as fortalezas e debilidades desse sistema de avaliação e se reflete sobre algumas alternativas para seu melhoramento, o que é valioso para revistas de língua espanhola.

Experimentos clínicos aleatorizados, o cómo evaluar las intervenciones / Randomized Clinical Trials in the Evaluation of Interventions

Introducción: Para la evaluación de una intervención (medicamento, terapia, técnica quirúrgica) se utilizan los experimentos clínicos aleatorizados, estudios que controlan de manera automática muchas fuentes de sesgos. Desarrollo: Deben tener siempre un grupo control; la asignación a los grupos de tratamiento debe hacerse mediante el azar, e idealmente, para la evaluación, debe cegarse al sujeto de estudio, al evaluador y a quien hace el análisis. Tanto la intervención experimental como la de control deben haber sido seleccionados con bases sólidas, y debe haber una incertidumbre genuina en relación con su efectividad y seguridad. Debe procurarse que las variables de medición del desenlace sean sólidas y objetivas (duras) o variables blandas que hayan sido obtenidas o transformadas mediante métodos ya definidos. Si no es posible cegar al sujeto o cegar la intervención, puede recurrirse a utilizar el método de doble simulación o a variables de desenlace duras...

Randomized Clinical Trials are used to evaluate interventions (drugs, therapies or surgical techniques), since they control for many possible sources of bias. Development: Clinical Trials must have a control group, assignation to treatment groups must be at random and it is ideal to blind the study subject, the researcher and the analyst for the evaluation. Both the experimental and the control interventions must be selected with solid bases, and there should be a genuine uncertainty about their effectiveness and safety. Outcome variables should be hard and objective, and if soft variables are used, they must be transformed using predefined methods to make them as objective as possible. If it is not possible to mask the subject or the intervention, double dummy methods should be employed or hard outcomes used. Key words: Randomized clinical trial, double-blind, hard outcomes, soft outcomes, assignation, ramdomization...