Studii interventionale Primele trialuri clinice randomizate efectuate in

Studii interventionale

• Primele trialuri clinice randomizate efectuate in anii 1940 sub egida Medical Research Council. → trialuri cu evaluarea streptomcinei in tratamentul tuberculozei (1948) • 1950 - Cochran si Cox publica primul tratat asupra trialurilor clincie randomizate • 1965 – Bradford Hill & Richard Doll Principles of medical statistics.

Studii interventionale Date obtinute de la grupuri Studiu de interventie in comunitate Date obtinute individualizat Trial clinic randomizat Trial in teren

Doua tipuri de studiu – unitatea evaluata si expunerea este: 1. individualizata 2. obtinuta populational • Studiile interventionale individualizate se impart dupa nivelul efectului : – Trialuri clinice randomizate (terapeutice), – Trialuri in teren (trialuri de profilaxie primara) subiectii sunt protejati printr-o masura profilactica si nu vor dezvolta boala. – Studii de interventie in comunitate - masura educationala, profilactica.

Trialul clinic randomizat (TCR) • experiment stintific utilizat pentru aprecierea eficacitatii si eficientei serviciilor de sanatate – Masoara eficacitatea terapeutica a unor proceduri terapeutice – Testarea produselor farmaceutice inainte de intrarea pe piata • Implica alocarea random (dependenta de sansa) a interventiei asupra subiectilor. – Randomizarea elimina eroarea sistematica de selectie (R) – Investigatorul realizeaza controlul expunerii (C) iar expunerea este specifica

Interventie + Efecte pozitive si negative Alocare random Fara interventie + Esantion - Obtinerea consimtamantului informat

TCR • Constituirea esantionului de studiu (consimtamant informat) – Criterii de includere si excludere – Definitie de caz, preferabil cazuri noi de boala – Masuratori initiale inainte de interventie • • Randomizare Aplicarea interventiei Masurarea efectului Analiza rezultatelor

TCR • Avantaje – Cea mai buna evidenta asupra relatiei cauza-efect – Singurul design posibil pentru introducerea oricarei interventii medicale terapeutice – Raspuns precis la problema de sanatate evaluata • Dezavantaje – – Cost: timp, resurse umane, bani Bariere: etice, frecventa evenimentului Poate aduce schimbari in practica medicala Restrictia la un singur raspuns.

Tipuri de trialuri clinice randomizate Martori istorici - Comparatie cu rezultate obtinute cu tratamentul conventional anterior Trial clinic fara randomizare - studiu simultan pentru grupul tratat si netratat dar fara randomizare TCR - studiu cu randomizarea subiectilor pentru interventie/non-interventie

TC fara randomizare Martorii si subiectii tratati sunt urmariti simultan. Alocarea interventiei este non-random Populatia --- Noua interventie ------> Endpoint Populatia--- Martori ------------> Endpoint

TC fara randomizare • Avantaje – Selectia interventiei bazata pe criterii clinice – Se castiga experienta cu interventia noua • Dezavantaje – Limitarea comparabilitatii – Studiile pe indivizi putini nu permit detectarea diferentelor – Selectia tratamentului cu deviere in favoarea unor subiecti.

TCR * "The Standard" * Studiu in paralel Noua interventie------> Endpoint Populatia ---> Randomizarea Martori---------> Endpoint

TCR • Avantaje – Sansa egala la tratament • Elimina biasul de selectie in alocarea pe grup tratat/netratat – Comparabilitatea • Egalitate a prezentei complianta si efect factorilor – Validitatea testelor statistice. legati de

Motive de a nu efectua TCR • Filozofice • Etice • Logistice

Interpretarea efectelor terapeutice se face pe baza riscului relativ, la fel ca în studiile de cohortă dar expunerea este reprezentată de tratament iar RR sub valoarea de 1 semnifică beneficiu terapeutic (pentru că riscul evenimentului negativ la “expuşi” este riscul la cei trataţi şi este mai mic decât la cei netrataţi). • Riscul relativ, RR = Riscul (decesului) la trataţi / Riscul (decesului) la cei netrataţi. Ex: RR = 0, 15/ 0, 20 = 0, 75 • Reducerea absolută a riscului, RAR = R netrataţi - R la trataţi. Ex. RAR = 0, 20 -0, 15 = 0, 05 sau 5% • Reducerea riscului relativ, RRR = 1 - RR Ex. RRR = 10, 75 = 0, 25 sau 25% • Număr de indivizi necesar de tratat pentru evitarea unui eveniment negativ= NNT = 1/ RAR – Ex. NNT = 1/0, 05 = 20 indivizi. De exemplu, hipolipemiantele au efecte benefice la NNT de aproximativ 25, adică tratând 25 de persoane se evită un accident coronarian major.

Trialul in teren • Persoane sanatoase dar cu risc de face boala • Grupurile comparate identic cu TCR dar un grup este protejat celalalt nu. • Masura este profilactica • Se evalueaza comparativ rezultatele pozitive (boala rara in grupul in care se face profilaxie) si reactiile adverse. • Eficacitate vaccinala EV=Inevaccinati - I vaccinati / Inevaccinati = 1 - Ivaccinati/Inevaccinati= 1 - RR (I=incidenta)

Privire de ansamblu asupra studiilor clinice realizate cu vaccinul Rota: date de eficacitate si siguranta Programul global de studii clinice vaccinul Rota pe 5 continente a inrolat peste >100, 000 sugari pana la acest moment Belgium Germany Finland USA Mexico Panama Costa Rica Canada Czech Republic France Venezuela Spain Brazil Italy Singapore Bangladesh Honduras Hong Kong Nicaragua Taiwan Dominican Rep. Colombia Peru Chile Argentina Thailand South Africa Vietnam Malawi India Korea

Vaccinul Rota – eficacitate, imunogenicitate si siguranta in Europa, studiul 036 124 centre in 6 tari din Uniunea Europeana

Vaccin rotaviral: rezultate privind eficacitatea Eficacitatea vaccinului Europa faza III 2 (dose 106. 5 CCID 50) GERV grava 96% (95% CI 90 -99) Spitalizari datorate GERV Orice GERV 100% (95% CI 82 -100) 87% (95% CI 80 -92) Spitalizari datorate oricarei GE 1 Vesikari 2 Vesikari T et al. PIDJ 200423: 937 -43 T et al. ESPID, Basel, Switzerland May 3– 5, 2006, Abstract 75 74% (95% CI 46 -89) CCID 50 – cell culture infecting dose 50% ffu – foci forming units

Vaccinuri rotavirus – istoric • Dezvoltarea vaccinurilor rotavirus a inceput in anii 1970 • Primul vaccin rotavirus a fost inregistrat in SUA in 1998: – Rotashield® (Wyeth – Lederle) – Rhesus-based tetravalent human reassortant vaccine (RRV-TV): vaccin uman reasortant tetravalent … – Retras in 1999 datorita legaturii cauzale cu invaginatia intestinala (“intussusception”) Asociatie temporala clara Murphy et al, N Engl J Med 2001 344 564– 72. Copyright © 200 x [2001] Massachusetts Medical Society. All rights reserved

Vaccinarea cu vaccinul Rota nu creste riscul de invaginatie intestinala Grup cu Vaccin Grup Placebo cohorta evaluata pt siguranta N=31, 673 cohorta evaluata pt siguranta N=31, 552 6 7 Cazuri Inv. Int. 0 31 zile Risc Relativ = 0. 85 (0. 30 ; 2. 42)* 9 0 100 zile Risc Relativ = 16 0. 56 (0. 25 ; 1. 24)* Fara risc crescut de invaginatie intestinala Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354: 11 -22 Macias, abstract, ICAAC, 2005, Washington, USA (poster) *95% CI

Studii de interventie in comunitate • Similar trialului clinic dar in conditii mai apropiate de realitate • Studii interventionale in comunitati intregi • Unitatea observata si analizata este grupul nu individul.

Fazele studiului de interventie in comunitate Populatia A Populatia B Se observa frecventa factorului de risc sau a bolii pentru o perioada de timp Alocare intamplatoare Interventia Masurarea efectului Martor Masurarea efectului

Studiul de interventie in comunitate Avantaje • Estimeaza realistic impactul masurii Dezavantaje • Pierderea controlului specific experimentului • Foarte costisitor • Tendintele multianuale nu apar evident.

Selectia grupurilor populationale • Scopul este sa se aprecieze in ce masura interventia are efect in teren • Reprezentativitatea esantioanelor comparate este importanta pentru generalizarea rezultatelor • Comunitatile trebuie alocate random la procedura profilactica/terapeutica evaluate initial si urmarite identic.

Randomizarea • Randomizarea survine la nivel de comunitate si nu individual • Scopul randomizarii este de a minimaliza efectul distorsionant al factorilor de confuzie, adica de a asigura comparabilitatea.

Efecte • Indicatori monitorizati “pe parcurs” – Evaluari de participare, prezentari media etc • Schimbarea asteptata: – Prevalenta factorului de risc – Atitudini si obiceiuri – Utilizarea serviciilor – Incidenta bolii

Community Intervention Trial for Smoking Cessation (COMMIT) • Proiect multicentric pentru a testa metode combinate de control a tabagismului • Conceput pentru marii fumatori care sa fie ajutati in abandonul si mentinerea abandonului fumatului • Conceput cu interventia media, organizatii mari, capabile sa intervina in comunitate in acest scop • Inceput in 1989 • 11 perechi de comunitati • 5 ani • Ratele de abandon a fumatului apreciate in cohorte de mari fumatori selectate random • Masuri intermediare de evaluare a activitatilor anti-tabac, a comportamentului a inclus studii transversale si evaluari a serviciilor oferite medicale si nemedicale de tip educational. Journal of the National Cancer Institute. 83(22): 1620 -8, 1991 Nov 20.

Surgical Mask vs N 95 Respirator for Preventing Influenza Among Health Care Workers: A Randomized Trial Loeb M, Dafoe N, Mahony J, et al JAMA. 2009; 302: 1865 -1871. Epub 2009 Oct 1 It became clear in April 2009 that a pandemic influenza with influenza A (H 1 N 1) would occur. Although the magnitude of the pandemic was difficult to predict, it was clear that preparedness by healthcare workers was urgently needed to preserve the workforce and to prevent viral transmission to highly vulnerable patients. The major mechanism of transmission is by aerosol particles, so the major prevention method is wearing a mask, either the N 95 respirator that is favored by the CDC or the surgical mask that has been deemed satisfactory by other groups. In view of a lack of data to document benefit or relative merit of different mask types, the Institute of Medicine (IOM) convened a meeting on September 3, 2009 and issued a report entitled Respiratory Protection for Healthcare Workers in the Workplace Against Novel H 1 N 1 Influenza A. [3] The conference noted that the N 95 respirators filter out 95%-99% of aerosol particles, but worker tolerance of these is poor; the supply is clearly inadequate; and most importantly, there are no quality studies comparing the relative merits of these 2 masks for the prevention of influenza.

Methods. The participants The purpose of the study was to compare the relative merits of surgical masks and the fit-tested N 95 masks for protecting healthcare workers from influenza. were nurses working in areas associated with extensive flu exposure at 8 hospitals in Ontario, Canada. These participants were randomly assigned to wear either surgical masks or fittested N 95 masks. Relative merits were based on the frequency of influenza demonstrated by polymerase chain reaction (PCR) or by seroconversion. Results. The study was stopped prematurely on April 23, 2009 due to the Health Ministry's recommendation for sole use of the fittested N 95 masks. At that point, analysis of data collected from the 422 nurses showed nearly identical results for laboratoryconfirmed influenza rates, 24% in those wearing surgical masks, and 23% for the N 95 masks. The relative merits of surgical vs fit-tested N 95 respirators for preventing influenza and other respiratory viruses are summarized in Table 4.

Surgical Mask (n = 212) N 95 Mask (n = 210) Laboratory-confirmed influenza 50 (24%) 48 (23%) -- RT-PCR proven 6 (3%) 4 (2%) -- HA titer increased ≥ 4 -fold to 2009 (H 1 N 1) 17 (8%) 25 (12%) Other respiratory viruses 20 (9%) 22 (11%) Influenza-like illness 9 (4%) 2 (1%) Absenteeism 42 days 39 days Laboratory and Clinical Outcomes Conclusion. The investigators concluded that "the use of the surgical masks compared with the N 95 respirators resulted in noninferior rates of laboratory-confirmed influenza. " Perspective. First, the study points out an obvious defect in the medical care scientific agenda. It is acknowledged that the mask issue is very important because nosocomial influenza and protection of the workforce are a very high priority, but precious few studies provide any data on the relative merits of these 2 very different masks. Nevertheless, the IOM, the CDC, and the Occupational Safety and Health Administration all endorsed routine use of the N 95 masks despite the fact that these masks were substantially more expensive; a major supply shortage was predicted; and tolerance by healthcare workers who had to wear them was poor. The study summarized above seems to demonstrate a case for surgical masks, but has not persuaded these authoritative sources. Reason for selection. This article was included because it deals with a rather fundamental issue in infection control -- one that is in great need of a tiny slice of the billions spent on biomedical research.

Probiotics in the critically ill: A systematic review of the randomized trial evidence; Petrof EO, Dhaliwal R, Manzanares W, Johnstone J, Cook D, Heyland DK Critical Care Medicine (Sep 2012) OBJECTIVE: Critical illness results in changes to the microbiology of the gastrointestinal tract, leading to a loss of commensal flora and an overgrowth of potentially pathogenic bacteria. Administering certain strains of live 76 bacteria (probiotics) to critically ill patients may restore balance to the microbiota and have positive effects on immune function and gastrointestinal structure and function. The purpose of this systematic review was to evaluate the effect of probiotics in critically ill patients on clinical outcomes.

Probiotics in the critically ill: A systematic review of the randomized trial evidence; Petrof EO, Dhaliwal R, Manzanares W, Johnstone J, Cook D, Heyland DK Critical Care Medicine (Sep 2012) • DESIGN: Systematic review • MEASUREMENTS AND MAIN RESULTS: We searched computerized databases, reference lists of pertinent articles, and personal files from 1980 to 2011. We included randomized controlled trials enrolling critically ill adults, which evaluated probiotics compared to a placebo and reported clinically important outcomes (infections, mortality, and length of stay). A total of 23 randomized controlled trials met inclusion criteria.

• Probiotics were associated with reduced infectious complications as documented in 11 trials (risk ratio 0. 82; 95% confidence interval 0. 69 -0. 99; p =. 03). When data from the seven trials reporting ventilatorassociated pneumonia were pooled, ventilatorassociated pneumonia rates were also significantly reduced with probiotics (risk ratio 0. 75; 95% confidence interval 0. 59 -0. 97; p =. 03). Probiotics were associated with a trend toward reduced intensive care unit mortality (risk ratio 0. 80; 95% confidence interval 0. 59 -1. 09; p =. 16) but did not influence hospital mortality. Probiotics had no effect on intensive care unit or hospital length of stay. Compared to trials of higher methodological quality, greater treatment effects were observed in trials of a lower methodological quality.

Probiotics in the critically ill: A systematic review of the randomized trial evidence; Petrof EO, Dhaliwal R, Manzanares W, Johnstone J, Cook D, Heyland DK Critical Care Medicine (Sep 2012) CONCLUSIONS: Probiotics appear to reduce infectious complications including ventilator-associated pneumonia and may influence intensive care unit mortality. However, clinical and statistical heterogeneity and imprecise estimates preclude strong clinical recommendations. Further research on probiotics in the critically ill is warranted.

Medicina bazata pe dovezi O abordare in formularea deciziei clinice prin care se cauta date din literatura medicala, se evalueaza critic rezultatele cercetarilor si apoi se alege cea mai adecvata interventie de adoptat.