Estudi observacional retrospectiu per avaluar la resposta clínica en pacients afectes de malaltia arterial perifèrica segons el compliment de les recomanacions terapèutiques farmacològiques de les guies de pràctica clínica per aquesta patologia

Les guies de pràctica clínica (GPC) proporcionen recomanacions per ajudar als professionals sanitaris i als pacients en el procés de presa de decisions en patologies específiques per millorar la qualitat de l'atenció al pacient. La malaltia arterial perifèrica (MAP) és un predictor de morbi-mortalitat cardiovascular. Aquesta tesi consta de dues parts que tenen en comú el tractament farmacològic de la MAP. La primera part, té com a objectiu revisar la qualitat de les GPC en el tractament farmacològic de la MAP. Es va realitzar una revisió sistemàtica de les GPC en el maneig farmacològic de la malaltia. Es van identificar les GPC publicades entre el 2003 i gener del 2015, en anglès, francès o castellà, a les bases de dades PubMed, Cochrane i TRIP database, i a pàgines web d'organitzacions que desenvolupen GPC i de societats científiques europees i americanes relacionades amb la MAP. Tres avaluadors independents van valorar la qualitat de les guies utilitzant l'instrument AGREE II (Appraisal of Guidelines, REsearch and Evaluation). Es van incloure un total de set GPC, publicades entre el 2006 i el 2012. La mitjana de puntuacions AGREE II de les guies va variar del 45% al 72%. Els dominis amb major puntuació van ser "Claredat a la presentació" i "Independència editorial" i el de menor puntuació "Aplicabilitat". Les classificacions i recomanacions utilitzades per avaluar la qualitat de l'evidència i la força o el grau de les recomanacions van ser molt heterogènies entre les guies, així com també hi havia variabilitat en les recomanacions dels fàrmacs vasodilatadors entre elles. El cilostazol va ser el fàrmac de primera línia més recomanat per les guies (71,4%), el naftidrofuril només el recomana la guia NICE com de primera línia (28,6%) i la pentoxifil·lina, quan es recomana, és de segona línia (28,6%). La segona part de la tesi, és un estudi observacional que avalua la morbi-mortalitat de pacients amb MAP que reben tractament amb pentoxifil·lina. Els pacients estan inclosos en un registre nacional multicèntric de pacients ambulatoris estables amb malaltia arterioscleròtica: registre FRENA (Factores de Riesgo y Enfermadad Arterial), iniciat al 2003. Al setembre del 2015, 5.204 pacients estaven inclosos al registre, dels què 1.732 tenien diagnòstic de MAP (33,2%) i 554 (32%) rebien tractament amb pentoxifil·lina; cap pacient rebia tractament amb naftidrofuril. Després d'un seguiment mitjà de 900 pacients-any, 56 pacients (3,2%) van desenvolupar infart de miocardi, 47 (2,7%) un ictus isquèmic, 68 (3,9%) pacients van patir amputació de l'extremitat, 19 (1,1%) van presentar un episodi de sagnat major i 117 (6,7%) van morir. No es van observar diferències estadísticament significatives entre els pacients que rebien o no rebien pentoxifil·lina en l'anàlisi multivariant, per a esdeveniments isquèmics (HR 0,91; IC 95% 0,64-1,29), sagnat major (HR 0,38; IC 95% 0,11-1,33) o mort (HR 1,32; IC 95% 0,90-1,94). Conclusions: Hi ha una gran variabilitat en la qualitat entre les guies i en llurs recomanacions sobre el tractament farmacològic dels pacients amb MAP. Una tercera part dels pacients amb MAP estan tractats amb un fàrmac de segona línia (pentoxifil·lina) segons les recomanacions de les guies, però el seu ús no s'ha associat a un augment de la morbi-mortalitat.Clinical practice guidelines (CPGs) provide recommendations to assist health professionals and patients in the process of making decisions for specific clinical conditions to improve the quality of the patient care. Peripheral artery disease (PAD) is a predictor of cardiovascular morbidity and mortality. This thesis consists of two parts that have in common the pharmacological treatment of peripheral arterial disease (PAD). The aim of the first part is to review the quality of CPGs in pharmacologic management of PAD. A systematic review of CPGs for the pharmacologic treatment of peripheral artery disease was performed. CPGs published between 2003 and January 2015 in English, Spanish or French were retrieved using PubMed, Cochrane and TRIP databases, guideline developer organizations websites, and European and American scientific societies related to PAD websites. Three appraisers independently assessed the quality of CPGs using the Appraisal of Guidelines, REsearch and Evaluation II (AGREE II) instrument. A total of seven CPGs, published between 2006 and 2012, were included. Average AGREE II guidelines scores varied from 45% to 72%. The highest scored domains were "Clarity and presentation" and "Editorial independence" and the lowest scored domain was "Applicability". The ratings and recommendations used to assess the quality of evidence and the strength or degree of recommendations were very heterogeneous between the CPG. Also was the extent of the drug recommendations regarding vasoactive drugs. Cilostazol was the first-line drug recommended by most guidelines (71.4%), naftidrofuryl as first-line treatment was only recommended by NICE guideline (28.6%) and pentoxifylline when recommended, was a second line option (28.6%). The second part of the thesis is an observational study that assesses morbidity and mortality of patients with PAD who receive treatment with pentoxifylline. Patients are included in a national multicentre registry of clinical data of stable outpatients with atherosclerotic disease, the FRENA Registry (Factores de Riesgo y Enfermadad Arterial), that began in 2003. In September 2015 there were 5.204 patients included in the registry, of which 1.732 (33.2%) had PAD diagnosis and 554 (32%) received treatment with pentoxifylline; no patient received treatment with naftidrofuryl. After a median follow-up of 900 patients-year, 56 patients (3.2%) developed myocardial infarction, 47 (2.7%) ischemic stroke, 68 patients (3.9%) underwent amputation of the limb, 19 (1.1%) showed a major bleeding episode and 117 (6.7%) died. No statistically significant differences were observed between patients receiving or not receiving pentoxifylline in multivariate analysis for subsequent ischemic events (HR 0.91, 95% CI 0.64-1.29), major bleeding episode (HR 0.38, 95% CI 0.11-1.33) or death (HR 1.32, 95% CI 0.90-1.94). Conclusions: There is great variability in quality between the guidelines and their recommendations on the pharmacological treatment of patients with PAD. One third of patients with PAD are treated with a second-line drug (pentoxifylline) according to the recommendations of the guidelines, but its use was not associated with increased morbidity and mortality

Assaig Clínic aleatoritzat de fase I en voluntaris sans per avaluar la seguretat de la vacuna terapèutica antituberculosa RUTI

Es va avaluar la seguretat de quatre dosis diferents (5, 25, 100 i 200 µg de FCMtb) d'una nova vacuna anti-tuberculosa (RUTI) en voluntaris sans comparant-la amb placebo amb un assaig clínic de fase I (n=24), unicèntric, doble cec, emmascarat, aleatoritzat (2:1), controlat amb placebo, seqüencial, d'escalada de dosi, administrant dues dosis de vacuna separades per 28 dies. Noranta-nou % dels esdeveniments adversos van ser lleus. Cefalea, dolor al lloc d'inoculació i fasciculacions van ser els esdeveniments locals més freqüents. Els grups de dosi de 5 i 25 µg de FCMtb van presentar la millor relació benefici/risc, sent d'elecció per a futurs estudis de fase II

HIVconsv Vaccines and Romidepsin in Early-Treated HIV-1-Infected Individuals: Safety, Immunogenicity and Effect on the Viral Reservoir (Study BCN02)

Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control

Pilot, double-blind, randomized, placebocontrolled clinical trial of the supplement food Nyaditum resae® in adults with or without latent TB infection: Safety and immunogenicity

Background. Nyaditum resae® (NR) is a galenic preparation of heat-killed Mycobacterium manresensis, a new species of the fortuitum complex, that is found in drinkable water, and that has demonstrated to protect against the development of active TB in a murine experimental model that develop human-like lesions. Methods. Double-blind, randomized, placebo-controlled Clinical Trial (51 volunteers included). Two different doses of NR and a placebo were tested, the randomization was stratified by Latent Tuberculosis Infection (LTBI)-positive (n = 21) and LTBI-negative subjects (n = 30). Each subject received 14 drinkable daily doses for 2 weeks. Results. All patients completed the study. The 46.3% of the overall reported adverse events (AE) were considered related to the investigational treatment. None of them were severe (94% were mild and 6% moderate). No statistical differences were found when comparing the median number of AE between the placebo group and both treatment groups. The most common AE reported were gastrointestinal events, most frequently mild abdominal pain and increase in stool frequency. Regarding the immunogenic response, both LTBI-negative and LTBI-positive volunteers treated with NR experienced a global increase on the Treg response, showed both in the population of CD25+CD39-, mainly effector Treg cells, or CD25+CD39+ memory PPD-specific Treg cells. Conclusion. This clinical trial demonstrates an excellent tolerability profile of NR linked to a significant increase in the population of specific effector and memory Tregs in the groups treated with NR in both LTBI-positive and negative subjects. NR shows a promising profile to be used to reduce the risk of active TB

Pilot, double-blind, randomized, placebo-controlled clinical trial of the supplement food Nyaditum resae^® in adults with or without latent TB infection: Safety and immunogenicity

<div><p>Background</p><p>Nyaditum resae^® (NR) is a galenic preparation of heat-killed <i>Mycobacterium manresensis</i>, a new species of the <i>fortuitum</i> complex, that is found in drinkable water, and that has demonstrated to protect against the development of active TB in a murine experimental model that develop human-like lesions.</p><p>Methods</p><p>Double-blind, randomized, placebo-controlled Clinical Trial (51 volunteers included). Two different doses of NR and a placebo were tested, the randomization was stratified by Latent Tuberculosis Infection (LTBI)-positive (n = 21) and LTBI-negative subjects (n = 30). Each subject received 14 drinkable daily doses for 2 weeks.</p><p>Results</p><p>All patients completed the study. The 46.3% of the overall reported adverse events (AE) were considered related to the investigational treatment. None of them were severe (94% were mild and 6% moderate). No statistical differences were found when comparing the median number of AE between the placebo group and both treatment groups. The most common AE reported were gastrointestinal events, most frequently mild abdominal pain and increase in stool frequency. Regarding the immunogenic response, both LTBI-negative and LTBI-positive volunteers treated with NR experienced a global increase on the Treg response, showed both in the population of CD25+CD39-, mainly effector Treg cells, or CD25+CD39+ memory PPD-specific Treg cells.</p><p>Conclusion</p><p>This clinical trial demonstrates an excellent tolerability profile of NR linked to a significant increase in the population of specific effector and memory Tregs in the groups treated with NR in both LTBI-positive and negative subjects. NR shows a promising profile to be used to reduce the risk of active TB.</p></div

Evolution of the PPD-stimulated T cells in TST-positive volunteers.

<p>Treatment groups are represented in black, red and blue, corresponding to Placebo, low dose and high dose Nyaditum resae^® respectively. P- values calculated by Wilcoxon matched pairs test. Plots are shown with median, IQR and minimum/maximum values.</p

Evolution of the PPD-stimulated T cells in TST-negative volunteers.

<p>Treatment groups are represented in black, red and blue, corresponding to Placebo, low dose and high dose Nyaditum resae^® respectively. P- values calculated by Wilcoxon matched pairs test. Plots are shown with median, IQR and minimum/maximum values.</p

Comparison of the median (IQR) number of AE by groups.

<p>Comparison of the median (IQR) number of AE by groups.</p

Chronogram and monitoring plan.

<p>Chronogram and monitoring plan.</p

Number of subjects presenting possible or probable related adverse events.

<p>Number of subjects presenting possible or probable related adverse events.</p